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COPD The definition of COPD, Chronic bronchitis, Emphysema, Cor-pulmonale

Risk factors of COPD

1. Cigarette Smoking & passive smoking

2. Atopy & Airway Hyperreactivity (AHR)

3. Air Pollution

4. Occupational Exposure

5. Infections

6. Growth, nutrition & socioeconomic status

7. Alpha-1 Antitrypsin deficiency

PATHOLOGYChronic bronchitis

1. The changes that occur in the central (large) airway in chronic bronchitis

2. Peripheral Airways Obstruction.

3. Bronchial biopsy studies, BAL, spontaneous or induced sputum

4. Emphysematous Lung Destruction

1. Centriacinar emphysema,

2. Panacinar emphysema/pan lobular emphysema

3. Distal acinar (para septal)emphysema

4. Other types of emphysema have been described

Bullous emphysema

Irregular emphysema

Pseudo emphysemasThe structural basis of airflow obstruction in COPD

PATHOGENESIS OF COPD1. Inflammation in COPD

1. Inflammatory cells

2. Inflammatory mediators

2. Mechanisms of Lung Damage in COPD

1. Mechanisms of mucus hyper secretion

2. Mechanisms of airway narrowing and fibrosis:

3.Mechanisms of parenchymal destruction:

1. Proteinase- Antiproteinase Imbalance.2. Increased oxidative stress

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3. Mechanisms of vascular damage

COPD

Definition of COPD..

COPD is preventable & treatable disease characterized by airflow limitation that is not fullyreversible with bronchodilators caused by cigarette smoker. The airflow limitation is usuallyprogressive and associated with an abnormal inflammatory response of the lungs to noxious

particles or gases with partial hyperreactivity. Although COPD affects the lung, it also produces

significant systemic consequence, and it is due to chronic bronchitis and emphysema.

(COPD) is probably the 4th commonest cause of death in middle aged to elderly men after IHD,

lung cancer and cerebrovascular disease.

Chronic bronchitis

Defined clinically by recurrent mucoid or mucopurulent expectoration, occurring on most days

for a minimum of 2 months of the year for 2 consecutive years in absence of other causes ofcough and expectoration.

The pathological basis of chronic bronchitis is mucus hyper secretion secondary to hypertrophy

of the glandular elements of the bronchial mucosa

1. Simple chronic bronchitis: chronic mucoid hyper-secretion

2. Mucopurulent bronchitis: sputum persistently or intermittent mucopurulent

3. Obstructive bronchitis: persistent widespread airway narrowing

Emphysema

1. Pathological definition,which is a condition where there is permanent destructiveenlargement of the airspaces distal to the terminal bronchioles without obvious fibrosis (to

exclude enlarged air spaces associated with gross fibrosis as in IPF).

2. Physiologically definition: as disease ch. by loss of elastic recoil & thus lung compliance

Cor-pulmonale : RT. ventricular hypertrophy with or without failure due to chest diseases

A. Pathological definition: Hypertrophy of the RT. Ventricle resulting from diseases affectingthe function / or structure of the lungs, except when this pul. alterations are the results of

diseases primarily affect the function of the LT side of the ht e.g. congenital heart diseases.

B. Clinical definition: alterations of the function / or structure of the RT. Ventricle resulting

from diseases affecting the function / or structure of the lungs, except when this pulmonaryalterations are the results of diseases primarily affect the function of the left side of the heart

e.g. congenital heart diseases.

Acute exacerbation of COPD was defined as the presence of any one of the following threesymptoms:

1. Increased cough and sputum volume

2. Increased sputum purulence

3. Increased dyspnoea.

4. In addition, pt. may have one or more symptoms of fever, malaise, fatigue and chest

congestion.

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Severity of acute exacerbations of COPD was defined astype 1 when patients had all threesymptoms, type 2 when patients had any two out of three symptoms, andtype 3 when

patients had any one of three symptoms.

Risk factors of

COPD

Established Probable Possible

Cigarette smoking

Occupational Exposure

1 antitrypsin deficiency

Air-pollution

Poverty

Childhood exposure smoke

Alcohol

Airways hyper reactive.

Low birth weight

Childhood resp. infection

Family history

Atopy ,IgA non sector

Blood group A.

Proposed Risk Factors for COPD

Risk Factor Comment

Increasing ageVentilatory impairment 1ry reflects cumulative lifetime smoking

history

Gender After standardization for smoking, males more at risk than females.

Smoking habitSome relation to number of cigarettes smoked /day and cumulative

pack-years.

Environmentalpollution

Large differences in urban and rural death rates; particulars more

important than photochemical pollutants.

Occupation

Many dusts cause mucus hyper secretion; persistent obstruction

develops in coal and gold miners, farmers, grain handlers, cement

and cotton workers; cadmium workers have increased risk of

emphysema.

Socioeconomicstatus

More common in persons of low socioeconomic status.

Diet High fish intake may reduce risk in smokers.

Genetic factors Homozygous 1-antitrypsin deficiency is the strongest single risk.

Birth weight andchildhoodrespiratory illness

Low birth weight presages low FEV1 and high COPD mortality in

later life; chronic childhood disease predisposes to chronic adult

disease.

Recurrent

bronchopulmonaryinfections.

Cause short-term decline in lung function, but not shown toaccelerate long-term decline in otherwise healthy smokers.

Allergy and airway Increased blood IgE and eosinophils and hyper responsiveness found

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hyperresponsiveness

in smokers, but significance as risk factors may be confined to a

subgroup of smokers.

Risk Factors for the Development of COPD

1. Cigarette Smoking

The most important risk factor in the development of COPD is cigarette smoking (80-90%)

with other types of tobacco smoking also being strong risk factors.

Many of other factors act as modifiers of the host response to cigarette smoke.

Age of starting smoking, total pack year, and current smoking status are predictive for

COPD mortality.

Not all people who smoke, however, develop COPD (may be only 10-15%); and not all

patients with COPD are smokers or have smoked in the past

The effects of cigarette smoke on the lung are:-

1) Cigarette smoking causing mucosal gland hypertrophy chronic mucous hyper-secretiontogether with inhibitory effect on mucociliary clearance stagnation of secretion with

superimposed infection associated with mucosal edema progressive persistent airflow

obstruction.

2) Smoking increases respiratory infections by damage immunological defenses by IgA &IgG. It increase bacterial adherence of pneumococcal pathogens to mucosal surface airways.

3) The effects of smoking on the Oxidant / /anti Oxidant balance are

Cigarette smoke has been found to attract inflammatory cells into the lungs asindicated by no. of neutrophil and macrophages in BAL from smoker's lung.

Smoking stimulates alveolar macrophages to release of neutrophil chemo-attractant

which release of the proteolytic enzyme elastase from neutrophil. Elastase breakdown

elastin (a normal structural component of lung tissue) but normally, the lung is

protected from the destructive effect of elastase by 1antitrypsin (AAT).

Inactivation of proteinase inhibitor by release reactive O2 radicals protease anti-protease imbalance more lung destruction by elastase & development of COPD ,and in particular emphysema

Attracts more cells and stimulates the release of more elastase than can be inhibited by

the circulating levels of AAT

Oxidant / anti oxidant imbalance in airspace epithelium and the injury

4) Smoking impairs pulmonary function, lung diffusion, blood oxygenation and oxygen

transport to tissues

5) Susceptible smokers (may be only 10-15%) show a accelerated decline rate of lungfunction (50-90 ml of FEV1/year compared with 20 ml of FEV1/ year in healthy non-smokers less than 30 years of age and 20-30 ml of FEV1/year after the age of 30 in non-

smokers). There are other confounding factors that complicate the relation between numbers

of cigarettes smoked and rate of decline of FEV1:

The extent to which smoke is inhaled

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The constituents of cigarettes ( tar, nicotine and other)

6) Tobacco smoking increase respiratory epithelial permeability which allow penetration of

allergens into airway wall increase IgE AHR

7) Increased air way resistance occurs after smoking only one cigarette, which can be blocked

by atropine, suggesting that it could be an irritant receptors reflex-induced phenomenon.

Effects of smoking cessation:

1. Persistent cough and sputum production results from bronchial gland enlargement in

proximal conducting airways are improve following cessation of smoking

2. Subjects with mild airways obstruction:

Slight improvement in FEV1 in 1st month afterstopping smoking, butsubsequently slower decline than in continuing smokers. Short term studies of

stopping smoking have shown improvement in small airway test, such as the

single breath nitrogen test, although changes in maximum expiratory flow-

volume curves have been variable

Persistent airflow obstruction arises from damage to peripheral airways & air

spaces are persistent aftercessation of smoking. By the time subjects aresymptomatic with breathlessness, they will have already severe impairment of

lung function, and stopping smoking at this stage may extend their life

expectancy but may not improve their symptoms.

3. Severe COPD: stopping smoking leads to improvement in cough, and sputum production,

but no change in FEV1

Passive Smoking

1. The harmful effects of smoking is not only limited to smokers, but the passive

smokers are adversely affected by the environmental tobacco smoke by increasing the

lungs' total burden of inhaled particles and gases.

2. This smoke (called side stream smoke) is actually higher in concentration oftoxic substances than exhaled smoke (mainstream smoke). However, it has been verydifficult to judge how much smoke is passively inhaled and what effects this passively

inhaled smoke has on the lungs.

3. Recently, it has been possible to assess the degree of exposure by measuringlevelsofthe nicotine metabolite, cotinine, either in the blood, saliva or urine.

4. The evidence suggests that respiratory infections and respiratory symptoms aremore common in children in households where one or both parents smoke. Also, there is a

small but significant difference in the prevalence of respiratory symptoms and lung

function in adults and children who are regularly exposed to passive smoking.

5. Maternal smoking in pregnancy is associated with low birth weight.

2. Atopy and Airway Hyperreactivity (AHR)

The role of AHR in pathogenesis of airway obstruction remains unclear. Numerous studies

found that smokers have higher IgE level and eosinophil count than non smokers; however

the levels are not as high as those seen in asthmatics.

It has been suggested that persistent airway obstruction in middle aged subject may be oftwo types:

(1) Dutch Hypothesis

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(2) "Two-type Hypothesis" or "Overlap syndrome"

A. Dutch Hypothesis:

1. Proposed that there is a genetically determined predisposition to develop allergy, bronchial

hyper-responsiveness and eosinophilia, According to this Hypothesis, an individual develops

asthma, bronchitis or emphysema is a result of genetic and environmental factors that are

modulated by age and gender.2. BHR may follow, rather than precede, the onset of smoking or other environmental insults

and thus may be more a result of smoking-related airways disease than a true risk factor.

AHR important in pathogenesis of persistent airway obstruction.

3. Such hyperreactivity is inversely related to FEV1, and evidence is steadily accumulating that

it is predictive of an accelerated rate of decline of lung function in smokers. But its possible

role as a risk factor that may predispose to the development of COPD in smokers or others is

unclear

B. "Two-type Hypothesis" or "Overlap Syndrome"

The "Two-type Hypothesis", which includes a Dutch-type, termed "Chronic Asthmatic

Bronchitis"or"Overlap Syndrome" which leads to "Chronic Obstructive Bronchitis and

Emphysema". Schools emphasis the inter-relationship between bronchial

hyperreactivity (atopy), infection and smoking.So focus has recently been placed intrying to identify the population most at risk of developing COPD.

It has been suggested that sensitization to tobacco smoking or pneumococci resident in

lower respiratory tract results in increase IgE AHR which may results from

structural changes or

Tobacco smoking increase respiratory epithelial permeability which allow penetration of

allergens into airway wall

increase IgE

AHRThe differences between AHR in smokers COPD& atopic asthmatic patients.

AHR in atopic asthma AHR in smoker's COPD

Age Occur in infancy, childhood and young atopicpatient (+ve skin test)

Occur more commonly in middle

aged than young non- atopic smokers

FEV1 AHR is present in those within normalbaseline respiratory function

There is strong relationship bet.

baseline FEV1 &AHR

PEFR There is strong relationship between AHRand diurnal variation in PEFR

No relationship

Eosinophils There is relationship between AHR andeosinophilic count

No relationship

Severity of AHR More severe Less severe

challenge test diagnostic Normal

B-agonists &anti-muscarinicdrugs

B- agonist have much larger short term effect

on attenuating AHR than anti-muscarinic

drugs

Anti-muscarinic drugs may have

more important effects and thus be

more useful in smoking COPD

NSAID May have a role No effect on AHR in smokers

Corticosteroid 2-3 months effectively attenuate AHR Ineffective in smokers mild airway

obstruction

No evidence of an increased prevalence of a family history of allergic disease nor anincreased prevalence of positive skin test to common aeroallergens in smokers.

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Smoking is not rare in asthmatic, but it dose not appear to be a risk factor for thedevelopment of asthma in middle ages. Indeed asthma may first develop after smoking

cessation.

Evidence indicated AHR in COPD is acquired and not constitutional are:

1. The difference to corticosteroids response in asthma and COPD suggest, but do not prove,

that AHR in smokers may be acquired rather than constitutional.2. Relationship between increased IgE levels and age and pack-years smokes.

3. IgE levels decreased after smoking cessation.

There are several possible mechanisms for the increased AHR

1. Structural changes increased airway thickening airway narrowing increase

airway resistance for a given shortening of airway smooth muscle.

2. Central deposition of inhaled aerosols as a result of airway obstruction

3. Loss of airway wall support as a result of loss of alveolar wall in emphysema

4. Increase respiratory epithelial permeability increase airway edema AHR

3. Air Pollution

Outdoor air pollution is very heterogeneous and is different in different areas. It

is mainly ofparticulates and gaseswith some background radioactivity.

1. The particulates and gaseous components:

a. The particulates mainly originate fromthe incomplete burning of solid fuels and diesel, ash and fine dusts. The main gaseouscomponents are the various oxides of sulphur, nitrogen and carbon, hydrocarbons andozone.

b. High concentration of sulphur dioxide

(150g/ m3) or similar concentrations of particulate air pollution (black smoke) was

associated with increase morbidity and hospital admission in patients with COPD. Levels of

sulphur dioxide or black smoke in excess of 500g/ m3 would be expected to increase

mortality among elderly and those with poor cardiopulmonary reserve.

c. The fine particles in air pollution with

aerodynamic diameter or less than10um or the ultra-fine particles with nanometer diameter

may have properties related to size, acidity, or its ability to generate oxidant increaseairway epithelium permeability airway inflammation pro-coagulant state and hence

increase cardiovascular mortality.d. Studies from the UK and USA have

shown a relationship between levels of atmospheric pollution and respiratory problems

(particularly cough and sputum production) in both adults and children,

e. Some studies have reported lower levels

of lung function in adults living in highly polluted areas and this seems related to pollution

by acidic gases and particulates. As with the problem of smoking, there will be individuals

who are more susceptible to the effects of atmospheric pollution than others.

2. Photochemical air pollution: There is association between exacerbation of airway diseasesand photochemical air pollution (nitrogen dioxide and ozone), mainly in asthma, noassociation between ozone and death from respiratory diseases.

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4. Occupational Exposure

1. Any occupation in which the local environment is polluted with the before mentioned

gases and particulates increase the risk of developing of COPD. In addition, there is

evidence that cadmium and silica also increase the risk of COPD. This is especially true ifthe subject smokes. Cadmium is a trace component of cigarette smoke (smoking induced

emphysema can not attribute to it).

2. Occupations at risk include coal miners, workers who handle cement, metal workers, grain

handlers, cotton workers, welding fumes, and workers in paper mills. However, the effect

of smoking far outweighs any influences from the work environment.

3. There is relationship between occupational dust exposure and the development of hyper

secretion of mucus.

4. The accumulating evidence for an association between coal-dust exposure and the

development of COPD led the UK to the establishment of COPD as a disease considered

for compensation in miners. The criteria for compensation are working underground for

more than 20 years and a reduction of FEV1 of at least 1L from the predicted value.

5. Chronic broncho-pulmonary infections

5. Since pt. with chronic bronchitis often have bacteria in their sputum, recurrent

bronchopulmonary infections results in damage to airways and progressive airways

obstruction. However, prophylactic antibiotic to prevent recurrent infective exacerbations

did not slow the decline in lung function.

6. Acute bronchopulmonary infections have an association with an acute decline in lung

function, which may persist for several weeks but which usually recover completely.

Studies failed to demonstrate association between annual rate of decline n FEV1 and

recurrent bronchopulmonary infections.

7. Intra-luminal airspace inflammation is characteristics of chronic bronchitis. PeripheralWBCs which is higher in 30% higher in smokers than non-smokers has inverse

relationship with FEV1.

8. Chest illness in early childhood appears to have an association with chronic respiratory

morbidity and impaired pulmonary function in adulthood. It is unclear whether these

episodes of infection in early life cause lung damage or it reflect increased susceptibility to

lower respiratory tract infection.

Types of organisms:

1. The role of viral infections of upper and lower respiratory tract in the pathogenesis of

COPD remains to be clarified. Viral infections in the lung enhance inflammation and

predispose to AHR.

2. There is increasing evidence between early childhood infections and increase respiratory

symptoms and lower lung function in adulthood. The viruses that have been implicated

are adenovirus, RCV, influenza and para influenza. Once COPD is established,repeated infective exacerbations of airflow obstruction, either viral or bacterial, may

speed up the decline in lung function.

3. Branhamella catarrhalis, Haemophilus influenza and streptococcus pneumonia,

they are frequently isolated from mucopurulent than from mucoid sputum in chronic

bronchitis. They are frequently present in nasopharynx of normal people but tend to

spread into the lower respiratory tract in winter and after cold.

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6. Growth, nutrition and socioeconomic status

1. Nutrition may affect both growth and impairment in ventilatory function. Impaired growth

in utero may be a risk factor for development of chronic respiratory diseases

2. A relationship between heavy alcohol intake and a risk of impaired ventilatory function have

been reported.

3. The association between childhood respiratory illness and ventilatory impairment inadulthood is probably multifactorial and may be due to:

a. Low socioeconomic status, poorer housing and poor nutrition (low intake of vitamin C

and low plasma level of ascorbic acid) and use of fossil fuels for heating without

adequate ventilation.

b. Higher prevalence of smoking in the lower socioeconomic status and employment in

jobs where they may be at risk from occupational exposure.

c. Residence in areas of high pollution.

7. Alpha-1 Antitrypsin Deficiency

1-antitrypsin (AAT) or 1-protease inhibitor (1-Pi) is a polymorphic glycoprotein;

composed of 394 amino acids and 3 carbohydrate side chains.

The activity of the protein is critically dependent on the methionine-358, serine-359

sequence at its active sites.

Its main role is the inhibition of neutrophil elastase.

AAT is synthesized in the liver, and increase from its usual plasma concentrations 2 gm/ L

as part of acute-phase response.

Most of the lung AAT is derived from plasma, although monocytes and macrophages can

also manufacture the protein. AAT is synthesized in the liver and the defect is one of cellular transport from liver cell into

the blood stream (which transports AAT to the lungs). The accumulation of AAT complexes

can damage the liver, whereas the deficiency of AAT fails to stop the destruction of lung

parenchyma giving rise to destruction of the alveoli and the eventual development of

emphysema or bronchiectasis.

AAT deficiency account for probably less than 5% (1-2%) of all cases of COPD. But rises to

greater than 50% in patients presented with severe disease who less than 40 years of age.

Alpha-1 Antitrypsin deficiency:

1. Is an inherited autosomal recessive disorder and transmitted as homozygoteor heterozygote deficiency of gene.

2. Deficiency is caused by mutations in the SERPINA-1 gene, located on

chromosome 14. There are over 70 known mutations that occur at the SERPINA1 gene

resulting from changes in amino acid sequence. A common mutation that creates the Z

allele involves a switch in amino acids glutamic acid is replaced by lysine at position 342

(Glu 342 Lys).

This gene has many different versions (alleles) that produce different amounts of AAT.

1. The MM phenotype:produces normal levels of the AAT protein (2 gm/ L)

2. The MS phenotype produces moderately low levels(1.6 gm/ L), no risk for emphysema

3. The MZ phenotype produces very low levels.(1.2 gm/ L), no risk for emphysema

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4. The SS phenotype produces very low levels.(1.2 gm/ L), no risk for emphysema

5. The SZ phenotype produces very low levels.(0.8 gm/ L), high risk for emphysema

6. The ZZ phenotype produces very low levels.(0.4 gm/ L), high risk for emphysema

The alleles are expressed in a co-dominant manner that means that a person with MZ has

levels of AAT that are between the levels of those people who have alleles MM or ZZ.

Individuals who have at least one normal allele (MZ or MS) or two copies of S (SS) usually

produce enough AAT (about 60% of the average normal) to protect the lungs but do have an

increased risk of lung disease. The risk is particularly high if they smoke.

Individuals who inherit the Z allele from each parent (ZZ) have very low AAT (about 10-

20% of the average normal) and are at a higher risk of developing emphysema and liver

disease. And at follow up shown a greatly accelerated decline in FEV1, but with large

variation between individuals.

The Z deficiency state is associated with PAS positive inclusion bodies in the liver, which

represent accumulations of the AAT proteins. Although liver and mononuclear cells from

these patients can manufacture normal amounts of mRNA, and the protein can be translated,there is little secretion of proteins.

Z AAT gene is normal except for a single point mutation resulting from substitution of

guanine for adenine in the DNA sequence that codes for amino acid at position 342 on

molecule change in amino acid sequence from glutamic to glycine alteration of the

normal hinge mechanism at this region spontaneous polymerization of the protein

large polymers of AAT accumulate in liver and are unable to pass through the rough

endoplasmic reticulum impairing AAT secretion.

There is a clear association with smoking

Life expectancy of subjects with AAT deficiency is significantly reduced especially if theysmoke.

The states they produce have been classified as:

a. Normal,associated with normal serum levels of normally functioning

b. Deficient,associated with serum levels lower than normal;

c. Null,associated with undetectable serum

d. Dysfunctional,in which is present at normal levels but does not function normally.

The pattern of emphysema in AAT deficiency differs slightly from that of smoking inducedpure emphysema in that AAT deficiency produces pan lobular emphysema affectingpredominantly the lower lung fields, and smoking produces centrilobular emphysemausually affecting the upper lung fields initially.

Not all people with PiZZ have very low levels of AAT. Only serum levels below 35% ofnormal level are at risk of developing emphysema, but PiZZ subjects who smoke have a

greatly increased risk of developing emphysema, especially at an early age. Few patients

identified as PiZZ live beyond their sixth decade and escape the development of progressive

air way obstruction.

Subjects who are PiMZ may also have reduced levels but not as low as PiZZ, and are notthought to be at more risk from developing emphysema than PiMM subjects.

Clinical picture: - in homozygous Pi ZZ

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1. Progressive dyspnoea Severe AAT deficiency leads to premature emphysema, often withchronic bronchitis and occasionally with bronchiectasis. The onset of pulmonary diseaseis accelerated by smoking (40 yr in smokers and 53 yr in nonsmokers)

2. Chronic bronchitis with recurrent infection

3. Weight loss is common, polycythemia and cor pulmonale occur late in the course of

disease, death occur in younger age in smoker decrease 50y4. Radiology: - bilateral symmetrical involvement of lung bases by emphysematous process

(Panacinar emphysema usually begins at the bases)

Diagnosis:-

1. Detecting a reduction in AAT on routine serum electrophoresis followed by Pi typingfor confirmation

2. Quantitation of AAT by radial immune-diffusion or by assessment of trypsin inhibitory

capacity

The circumstances in which the tests should be ordered are

1. Chronic bronchitis with airflow obstruction in a never-smoker

2. Bronchiectasis, especially in the absence of clear risk factors for the disease

3. Premature onset of COPD, with moderate or severe impairment by or before age 50

4. A predominance of basilar emphysema

5. Development of unremitting asthma, especially in a person under age 50 (screening is

indicated even in the presence of atopy)

6. A family history of alpha1-antitrypsin deficiency or of COPD onset before age 50

7. Cirrhosis without apparent risk factors

Treatment of AAT deficiency

1. Standard treatment of emphysema (bronchodilators, early use of antibiotics in infections)

2. The most important part of ttt of AAT deficiency is to avoid smoking. Affected individualsare far less likely to develop emphysema if they do not smoke. Not only is smoking a lung

irritant, which attracts white blood cells (and therefore neutrophil elastase) to the lungs, it

also prevents any AAT that is present in the lungs from working properly

3. Gene therapy to replace the defective SERPINA1 gene with a functional copy is currentlybeing investigated.

4. Danazol 600mg/d for 30 day: synthetic steroid increase level of AAT but not to levels highto protect them from emphysema

5. Attempts to develop synthetic anti-protease under trial

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PATHOLOGY of COPD

COPD comprises pathological changes in four different compartments of the

lungs:

1. Large airways: Chronic bronchitis

2. Small airways: Small airway disease.

3. Lung parenchyma: Emphysema.

4. Pulmonary vasculature. Pulmonary hypertension and Cor pulmonale

As a result of that there is still no clear consensus on weather the fixed airways

obstruction in COPD is largely due to inflammation and scarring of the small airways,

resulting in narrowing of airway lumen, or due to loss of support of the airways because of

loss of alveolar wall as in emphysema.

The pathologic hallmarkof chronic bronchitis is an increase in goblet cell sizeand number that leads to the excessive mucus secretion and airflow obstruction.

The pathologic hallmarkof emphysema is elastin breakdown with resultantloss of alveolar wall integrity is a frequent but not universal accompaniment. Finally, whenCOPD is complicated by hypoxemia, intimal and vascular smooth muscle thickening maycause PH, which is a late and poor prognostic development in COPD.

1. The changes that occur in the central (large) airway in chronic bronchitiswhich include trachea, bronchi and bronchioles down to airways that are 2-4 mm in internaldiameter in cases of chronic bronchitis include:-

Mass of submucosal gland is larger than goblet cells so most airways secretion is produced

by these glands.

Infiltration of the surface epithelium lining of the airways, gland ducts, and glands by an

inflammatory exudates of fluid and cells dominated by macrophages, CD8+T- lymphocytes,

and neutrophils. This chronic inflammatory process is associated with:-

A. Submucosal glands:

Hypertrophy and hyperplasia of the mucus-secreting glands with dilation of gland ducts

which results in an increased Reid Index.

It is mainly due to irritant action of cigarettes smoke (sometimes it may be due to

sulphur dioxide and nitrogen dioxide)

The hypertrophy of mucous glands is mainly in the larger bronchi and is evenly

distributed throughout the lungs.

Mucous gland hypertrophy can be quantified by:

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1. Reid index, which is the ratio of the distance between the basement membrane of

the airway epithelium and the cartilage to the thickness of the gland layer, normally

3: 1).

2. Measurements of the absolute gland mass independent on variation in bronchial

dimensions.

3. Sputum production correlates better with mucus gland area rather than Reidindex.

4. Neither sputum production nor gland size bears any relation to FEV1.

B. Goblet cells: In healthy people who have never smoked, goblet cells are seenpredominantly in the proximal airways and decrease in number in more distal airways, being

normally absent in terminal or respiratory bronchioles. Goblet cell increased in number and changein distribution in the surface epithelium with peripheral extension through the bronchial tree.

Moreover, they secrete a more acidic, highly sulfated mucous. In smokers, goblet cells not

only increase in number but extend more peripherally.

C. Surface epithelium:

Squamous metaplasia which not only predisposes to carcinogenesis but also disrupts

mucociliary clearance.

The presence of epithelial metaplasia or dysplesia may replace goblet cells so may

decrease their number in proximal airways in some smokers.

D. Airway smooth muscle: Hypertrophy of airway smooth muscle and connective tissue in the

airway wall, and a degeneration of the airway cartilage.

E. Acute infections:

Macroscopic picture:bronchial wall is inflammed, and there may be pus in the lumen.

Microscopic picture: bronchial walls show infiltration by acute and chronic inflammatorycells, dilatation and of the capillaries and edema, mucous membrane may become ulcerated,

with squamous epithelium replacing columnar epithelium in limited areas.

2. Peripheral Airways Obstruction (small airway disease) :

These airways include small bronchi and bronchioles

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Assessment of small airway disease:

A. There is several pathological changes in small air way that wereassessed using scoring system:

1. Occlusion of the lumen by pus and cells.

2. Presence or absence of mucosal ulceration.

3. Goblet cells hyperplasia.

4. Inflammatory infiltrate in the airway wall.5. Amount of fibrosis in the airway wall.

6. Amount of muscle.

7. Degree of pigmentation.

B. A quantitative approach by measuring the dimensions of smallairways.

3. Bronchial biopsy studies, BAL, Spontaneous or inducedsputum

1. Bronchial biopsy studies (bronchoscopy) Shown that:a. Activated T lymphocyte is prominent in the proximal airway wall.

b. Macrophages are also a prominent feature

CD8 suppressor T-lymphocyte subset rather than CD4 subsets predominates.There is

significant ve association between the number of CD8 in the airways wall and thedegree of airways obstruction as measured by FEV1 in smoker.

c. Bronchial biopsy in acute exacerbation of COPD shows increase number of

eosinophil in bronchial walls, but it do not appear to be degranulated. (less than that

found in bronchial asthma)

2. BAL:

a. Accumulation of macrophages in respiratory bronchioles (95% of total cell

count) is a characteristic finding in BAL of young adult cigarette smokers which is roughly

about fivefold more than BAL from non smoker.

b. Increased numbers of neutrophils in large airways.

3. Spontaneous or induced sputum:

a. Show increased chemotactic activity, partly due to IL-8 and other inflammatory

mediators such as TNF-.

b. Treatment with anti-inflammatory agent such as inhaled steroids can reducechemotactic activity of sputum (other study show no effect).

4. There is clear difference in cell population sampled by biopsy, BAL, spontaneoussputum and induced sputum in patients with COPD, in stable chronic bronchitis:

- BAL: neutrophils are high.

- Sputum: macrophages and lymphocytes are high:

- Eosinophils equal in the three techniques.

- Biopsy: lymphocytes where the predominant cells in submucosa.

Cigarettes smoking is associated with increased sequestration of neutrophilswithin the micro-circulation of the lungs; this increased sequestration of neutrophils is due to

decrease in deformability of circulating neutrophils in response to cigarette smoke, which

delays their passage through the lungs. The increased sequestration in and migration of

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neutrophils from systemic circulation in COPD involves up-regulation of cell- surface

adhesion molecules on endothelial cells and epithelial cells.

Studies of sputum and bronchial biopsy usually sampled proximal air way

but there is evidence that the same changes occur in small airways and perhaps even the

alveoli.

4. Emphysematous Lung Destruction Definitions of emphysema:

Conditions of the lung characterized by abnormal, permanent enlargement of airspaces, distal to

terminal bronchioles, accompanied by destruction of their wall without obvious fibrosis.

This is a pathological diagnosis more than clinical, t should be emphasize that clinical,

radiological and functional assessment of emphysema is no a sensitive methods for diagnosing

emphysema.

Limitations of definition of emphysema:

1. No agreed criteria for normal airway size by which abnormality can be assessed.

2. Without obvious fibrosis were included in definition to exclude enlarged airspace

associated with gross fibrosis (cryptogenic alveolitis), however:

a. Fibrosis identified in the wall of emphysematous airspaces.

b. Further more when sensitive techniques are used to measure collagen and elastin

in alveolar walls, there appears to be an increase in collagen in the lung parenchyma in

smokers, which is also the case in areas of emphysema compared to areas of relatively

normal lung.

c. Scanning electron microscopy has demonstrated fibrosis in association with end

stage emphysema.

3. Destruction of alveolar walls was included to exclude causes of hyper inflation

(pneumonectomy and chronic asthma). However, in an area of emphysema it is difficult to

distinguish between those due to hyperinflation from those due to destructive process.

Types of emphysema:

- Emphysema is traditionally subdivided based on the concept of the pulmonary lobulewhich is the smallest lung unit separated by fibrous setae, each lobule being composed of

4-8 terminal bronchioles and their distal alveolar ducts and sacs.

- Air space enlargement can identified macroscopically when it is greater than 1 cm

diameter.

- Three major types of emphysema are recognized according to the distribution within

acinar unit (centrilobular, panlobular, and para septal).

1. Centriacinar emphysema,

It is the most clinically important form of emphysema begins in the respiratory bronchioles

and spreads peripherally, predominantly in the upper zones of the upper lobes and superior

segment of lower lobes.

It is associated with more small airways disease and less loss of elastic recoil for any level

of respiratory function.

It had greater airway hyperreactivity than those with panacinar emphysema; the AHR in theformer correlated with the numbers of lymphocytes in the airways walls.

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Centrilobular emphysema is the form of centriacinar emphysema associated with

longstanding cigarette smoking which induces leukocyte and macrophage chemotaxis,

elastase release and activation and which contains oxidants that inhibit AAT leading to

elastic tissue breakdown.

Focal emphysema is the form of centriacinar emphysema that occurs in coal workers pneumoconiosis.

2. Panacinar emphysema/pan lobular emphysema

Relatively uncommon, which involves the (whole acinar unit); respiratory bronchioles, alveolar

ducts and alveoli,pred omin ant ly in lo we r lo be s.

This type of emphysema generally caused by AAT deficiency leading to proteolytic breakdown

of elastic tissue within alveolar wallsFocal panacinar emphysema at the lung bases may accompanycentrilobular emphysema in smokers.

It dose not appears to be present in early stages of all smokers.

There is still debate over whether centriacinar and panacinar emphysema represent

different disease processes, and hence have different etiologies, or whether panacinar

emphysema is a progression from centriacinar emphysema. There is certainly a clearer

association between cigarette smoking and centriacinar emphysema than with panacinar

emphysema.

The two common types of emphysema have different distributions within the lungs.

Centriacinar emphysema is more common in the upper zones of the upper and lower lobes,whereas panacinar emphysema may be found anywhere in the lungs but is more prominentat the base and may be associated with 1-AT deficiency. Both types of emphysema can occur

alone or in combination.

Centriacinar emphysema had more abnormalities in their small airways, than those

the predominantly panacinar emphysema. Moreover, the patients with centriacinaremphysema had greater AHR than those with panacinar emphysema.

Pathological assessment of severity of emphysema:

A. Macroscopically (resected lung specimens):

- Point counting technique,producing quantitative assessment of amount of lung

involved in emphysema.

- Paper-mounted- cross-sections of the lungs with varying degrees of emphysema that

were ranked from 0 (normal)- 100 (most extensive emphysema.

- Disadvantage of these techniques:Both techniques not assess pattern of emphysema.

And failed to identify airspace less than 1mm in diameter and therefore do not measuremicroscopic emphysema. This is important because when an alveolus, which is normally

240m in diameter, has enlarged to reach 1mm, 75% of the alveolar surface has been

destroyed.

B. Microscopically:

- Mean linear intercept technique, estimates the diameter of the airspace (distal airspace

size, Lm)

- Surface area of the alveolar or airspace wall per unit lung volume (AWUV).

C. Alveolar wall integrity : The bronchioles and small bronchi are supported by the attachment

to the outer aspect oftheir walls of adjacent alveolar walls. This arrangement maintains the tubularintegrity of airways. The integrity of the alveolar wall supports can be assessed by measuring the linear

distance between the alveolar wall attachments, the intra-alveolar wall attachment distance.

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3. Peri acinar emphysema: where the enlarged airspaces are along the edge of the acinar unit but only where itabuts against fixed structure, such as pleura or vessels. Occur less common than centriacinar or panacinar

emphysema, and is usually of little clinical significance, except when it occurs extensively in a subpleural

positions and may be associated with pneumothorax.

4. Distal acinar (para septal)emphysema:

Para septal emphysema occurs close to connective tissue septa and usually leadsto blebs on the lung surface which predispose to pneumothorax or to giant bulla within thelung substance cause severe compression of relatively uninvolved lung and impairing lung

function.

It can occur in quite young individuals, it involves distal airway structures.

Caused by focal scarring along pleura or interlobar setae destroying alveolar ducts, and sacs.

Upper Lobe > Lower Lobe.

Airspace enlargement with pulmonary fibrosis is commonly seen as an inconsequential

lesion adjacent to scars, but it may sometimes be severe with extensive fibrosing disease,

such as sarcoidosis or TB. The underlying fibrosis is usually evident radiographically, with extensive linearor nodular shadows accompanying increased transradiancy or bullae.

Vanishing lung it is extreme form of 1ry emphysema in patients who have progressive emphysematousbullae without cough, without bronchitis and die with respiratory failure with little or no evidence of

respiratory infection.

5. Other types of emphysema have been described

a) Bullous emphysema:

Definition: bullae represent localized area of emphysema that have overdistended, conventionally only lesion greater than 1 cm are described as bullae.

It is an exaggerated form of centriacinar or para septal emphysema.

Bullae arise in an area of lung that has been locally destroyed, althoughthis destruction does not always have to be as a result of emphysema and can also occur

from lytic or traumatic causes.

Bullae have been described in TB, sarcoidosis, AIDS and trauma.

In a minority of cases, around 20%, the surrounding lung is normal, butin the majority there is associated emphysema and COPD.

Types of bullae: Bullae have been classified according to their size andposition.

1. Type I bulla have a narrow neck, attached to a mushroom-like expansion into thepleural space;

2. Type II bulla have a broader neck and represent distension of a moderate areaofemphysema;

3. Type III bulla occur in an area of severe emphysema within the lung and have nopleural reflection.

Origin of bullae: remain obscure particularly in type I. types III, and IIIappears in areas of moderate to sever emphysema.

Mechanism of bullae formation: thee region of the local weakness inthe structures of the lung supplied by airways with a valvular structure, which allows air toenter these areas of the lungs and prevent its exits. However, there are several problems

with this theory:

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- It suggests that air enter areas of high pressure rather than to more complaint

lung.

- Direct measurements of pressure within the bullae at operation are very

similar to pleural pressure (-11 cm H2O during tidal breathing)

Differential diagnosis: the term bullae, cyst, cavity, and pneumatoceles

are used interchangeably:A. Cyst: generic term for an abnormal airspace greater than 1 cm in diameter, which can

be congenital or acquired, and lack an epithelial lining.

B. Cavity: is an acquired cyst with non- epithelial lining and a wall thicker than 3mm,usually arise following pulmonary infection or fibrosis.

C. Bullae: is an acquired enlarged airspace but has extremely thin wall.

D. Pneumatoceles: acquired air space, which reversed for small post-infective cysts thatresult from tissue lysis, such as in staphylococcal pneumonia.

Treatment: Sometimes surgical "bullectomies" are performed to removevery large bullae.

b) Irregular emphysema: It is a focal form of emphysema and is related to oldscarring. It is quite common but not generally clinically significant.

c) Pseudo emphysemas (do not fulfill real definition of emphysema)

1. Compensatory emphysema occurs in healthy part of the lung to compensate forreduction in size or function of diseased part or whole of lung 2ry to lobectomy,

collapse, and fibrosis. There is dilatation of airspace without destruction of alveolar

septa. Clinically: no diminished breath sound intensity.

2. Senile emphysema - age related variation in alveolar size, but no reduction inblood vessels or capillaries.

3. Mediastinal or SC emphysema (eg interstitial - traumatic extravasations of airinto lung stroma). There is subcutaneous crepitus.

d) Infantile emphysema.

e) Lobar emphysema with bronchial atresia.

f) McLeod's syndrome (unilateral emphysema of a lung or lobe due to localizedbronchiolitis or bronchitis).

Pulmonary Vasculature

Pulmonary vesselsbegin to change early in the natural history of COPD. As airflowlimitation increases and pulmonary vascular pressures increase, first with exercise and then

at rest, there is intimal thickening ofsmall pulmonary arteries , followed by medialhypertrophy in muscular pulmonary arteries.,increase in airway smooth muscle and theinfiltration of the vessel wall by mononuclear cells that include macrophages and CD-8lymphocytes.

As COPD worsens, the reorganization of the structure of the vessel wall continues with the

appearance of greater amounts of smooth muscle, proteoglycan, and collagen, which leads to

further thickening of the vessel wall. In advanced disease, the changes in the musculararteries may be associated with emphysematous destruction of the pulmonary capillary

bed in largepulmonary artery.

Pathological features of pulmonary vasculatures in COPD:

1. Main pulmonary artery show:18

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- Much increase in elastic lamina of acquired type (fibrous, irregular in width and

separated by wide space than that of aorta). Intimal atheroma may be present.

- May show aneurismal dilatation.

- Sometimes main pulmonary trunk laminated thrombus in about 20% of cases of

severe COPD at post mortem.

2. Elastic pulmonary arteries: atheroma medial thickening and dilatation.

3. Small pulmonary arteries show 3 components:

A. Extension of the medial muscle into the pulmonary arterioles (normally not contain

muscle)

B. Presence of longitudinal muscle in the intima, through process of proliferation muscle

may become thicker and may occlude the vascular lumen. Intimal fibrosis may occur

that may be severe so pulmonary arterioles develop muscularized media between two

elastic lamina.

C. External to the thickened elastic lamina is an area containing myofibroblast which

eventually replaced by fibroblastic tissue.

4. Capillary bed: As a result of loss of the alveolar surface area capillary bed isreduced.

5. Bronchial arteries:

- The bronchial arteries are often enlarged. In COPD, the bronchial venous circulationmay abnormal too.

- Normally, Venous blood from peripheral bronchi drain via pulmonary veins into LTatrium, whereas, larger proximal bronchi drain via bronchial vein intoRT atrium.

-

In emphysema: bronchial veins are distended and carry more returning blood thannormal, with onset of cor pulmonale increase pressure in great veins reversal ofblood flow broncho-pulmonary shunt aggravating hypoxia in systemic circulation.

The heart Develops RVH and dilation 2ry to pulmonary hypertension caused by COPD,

Right ventricle (RV):

a. The normal right ventricle (RV)is a thin-walled, distensible muscular pump thataccommodates considerable variation in systemic venous return without large changes in

filling pressure.

b. In response to chronic pressure overload by PH, the RV enlarges, primarily by

hypertrophy. In time, if the pressure load continues, the RV will fail, Relief of PHdiminishes the load on the RV, its filling pressures return to normal and COP once again

responds appropriately to the level of exercise.

c. Fulton index: ratio of the weight of left ventricle and inter-ventricular septum to that of

free right ventricle wall is decreased (normal 2.2).

d. Measurements of ventricular wall thickness alone are not considered accurate in the

assessment of right ventricular hypertrophy due to the complicating effects of ventricular

dilatation and heart failure.

The left atrial pressure is normal in cor pulmonale except when circulating

blood volume is increased or if cor pulmonale is complicated by LVF The left ventricle (LV):

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A. One hypothesis has been that LVH may be due to hypertrophy of the muscle

bands surrounding both ventricles and RT inerventricular dependence of septum.

However, there is no firm clinical support for this notion.

B. LVH may occur in patients with chronic cor-pulmonale by biochemical andanatomical changes including a decreased concentrations of nor-epinephrine, anabnormal histochemical appearance of the adrenergic nerve fibers, a depressed myofibril

adenosine triphosphate activity and an increased amount of collagen fibers

C. The more usual cause of LVF in cor pulmonale is independent disease of LV e.g.

independent atherosclerosis of the coronary arteries in elderly people

Other abnormalities:with increasing emphysema there is decrease in muscle and weight ofdiaphragm, enlargement of the renal glomeruli and carotid body enlargement

The structural basis of airflow obstruction in COPD may be summarized as follows:

1. Alterations in the glands of the central airways have little effect on spirometry.

2. Alteration of the small airways is a major cause of airflow obstruction.

3. Mononuclear cell inflammation in the respiratory bronchioles is the earliest lesion in young smokers.

4. Airflow obstruction in COPD is primarily irreversible and cannot be explained entirely on a structural basis;broncho-constriction is another mechanism.

5. Broncho-constriction is caused by disease of the small airways, which may be due to the effects of

inflammation, fibrosis, goblet cell metaplasia, & smooth muscle hypertrophy in terminal bronchioles are

important causes of airflow obstruction in those airways. Also the loss of alveolar attachments may have

an important role in the development of airways obstruction in early emphysema, but may be

less important in the overall severity of airflow limitation in the later stages of the disease.

Pathogenesis and cellbiology of COPD

1. Tobacco smoking is the main risk factor for COPD ( but it is clear that susceptibility to

the effects off cigarettes smoke determines the presence and severity of COPD since only 10-

20% of smokers develop the disease) , although other inhaled noxious particles and gases may

contribute. This causes an inflammatory response in the lung. This inflammation can then lead

to tissue damage if the normal protective and / or repair mechanisms are overwhelmed or

defective.

2. The majority of the work on the pathogenesis of COPD relates to the development of

emphysema and divers from the observation ofAAT deficiency and the development ofearly onset emphysema.

These two important observations form the basis of the protease-

antiprotease theory of the pathogenesis of emphysema.

The hypothesis states that in healthy lungs the release of proteolytic

enzymes from inflammatory cells does not cause lung damage because of the inactivation of

these proteolytic enzymes by an excess of inhibitors (antiprotease). However, in conditions of

excessive enzyme overload, or where there is an absolute or functional deficiency of

antiprotease and imbalance develops between proteases and antiproteases in favour of

proteases, leading uncontrolled enzyme activity and degradation of lung connective tissue in

alveolar wall (emphysema) In addition to

(1) Inflammation

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(2) An imbalance of proteinases and antiproteinases in the lungs

(3) Oxidative stress are also important in the pathogenesis of COPD.

The results of the lung tissue damage are mucus hyper secretion, airway

narrowing and fibrosis, destruction of the parenchyma (emphysema), and vascular changes

airflow limitation

PATHOGENESIS OF COPD

21

Smoking or noxiousagents

Lung inflammation

Host factors

Anti-proteinasesAnti-oxidants

ProteinasesOxidative stress

Lung damage

Repair mechanisms

Inflammation

Airflow Limitation

Parenchymal destruction

Loss of alveolar attachmentsDecease of elastic recoil

Small airway disease

Airway inflame. & remodelingMucous hypersecration

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(1) Inflammation in COPD

1. COPD is characterized by persistent inflammation throughout the airways and

parenchyma. COPD primarily affects the distal airways. Generally, inflammation

affects bronchioles at the level of the respiratory bronchiole extending to the alveolarwall. Airway walls are infiltrated with macrophages and lymphocytes. In contrast to

asthma, the airway lymphocytes tend to be CD8 + rather than CD4+ cells. The CD4+

cells that are present in COPD tend to be Th1 rather than the Th2 cells found in asthma.

2. Activated inflammatory cells release mediators that are capable of damaging lung

structures. These mediators include a spectrum of potent proteases, oxidants, &toxic peptides. The damage induced may further potentiate inflammation by releasing

chemotactic peptides from the extracellular matrix.

Multiplicity of Cells and Mediators Involved in COPD

a) Inflammatory cells

The inflammatory response in the airways and lung parenchyma in COPD is characterized by an

increase macrophages, T-lymphocytes (predominantly CD8+ T cells), andneutrophilsareincreased in and around bronchial glands, in stable COPD. There may also be an increase ineosinophilsin the airway walls and lumens in COPD exacerbations.

1. Macrophages

- There are increase macrophages in the large and small airways and lung parenchyma

of patients with COPD, as reflected in histopathology, (BAL), bronchial biopsy, and induced

sputum. In patients with emphysema, macrophages are localized to sites of alveolar wall

destruction.

- Macrophages produces : - LTB4, IL-8, and proteolytic enzymes matrix metalloprotease

MMP-12, MMP-1 (collagenase), and MMP-9 (gelatinase B). Activated macrophage-derivedTNF- which activate and amplifies neutrophil recruitment and accumulation in lung tissue

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by activation of neutrophil surface adhesion molecules. TNF- up regulates cytokine

production and is associated with COPD cachexia.

2. T-lymphocytes:

- Histopathology and bronchial biopsy studies show an increase T-lymphocytesthroughout the airways of patients with COPD, with the greatest increase CD8+

(cytotoxic) cells.- The role of T lymphocytes in COPD may be through the induction of apoptosis of

airway epithelial cells, mediated by CD8 cell releaser of TNF-, Perforin and granzyme-

B.

The number of both CD8 cells and neutrophils present in lung tissue is proportional to thedegree of airways limitation present in COPD.

3. Neutrophils:

Increase number of activated neutrophils is

found in sputum and BAL fluid of COPD patients little increase in airway or lungparenchyma.

The number of neutrophils in BAL fluid is

markedly increased during acute exacerbations of COPD.

The importance of neutrophils in COPD is

shown by the fact that neutrophils, but not macrophages, are increase in the BAL fluid of

COPD patients who have never smoked.

The role of neutrophils in COPD is not yetclear. They may contribute to both

1. Neutrophils secrete several proteinases, including neutrophil elastase, Cathepsin G,and proteinase which may contribute to parenchymal destruction (emphysema).

2. Neutrophils are likely involved in chronic mucus hyper-secretion by neutrophil

elastase and proteinase-3 which are also potent mucus stimulants.

3. Increased neutrophil sequestration in the pulmonary micro circulation in smokers has

the potential to cause lung injury without the need for cell migration into the airspace.

- Neutrophils derived from promyelobasts in the bone marrow and migrate through the

bloodstream to the respiratory tract, guided by neutrophil chemotactic factors such as

IL-8 and LTB4.

- Once in the lung, they adhere to endothelial cells in the bronchial and pulmonarycirculations, and then enter the airways or parenchyma.

- IL-8 promotes neutrophil chemotaxis and activation through binding to chemokine

receptors, on their cell surface.

- Neutrophils become activated to produce LTB4and the proteolytic enzymeselastase, proteinase, Cathepsin G, MMP-1, and MMP-9. Both TNF- and

neutrophil elastase promote IL-8 secretion from airway epithelial cells.

- Neutrophil survival in the respiratory tract may be increase by cytokines, such as

granulocyte-macrophage colony stimulating factor (GM-CSF).

- The increase in neutrophils in induced sputum is matched by an increasemyeloperoxidase (MPO) and human neutrophil Lectin, reflecting neutrophilactivation.

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Mechanism of Neutrophil Inflammation in COPD

4. Eosinophils:

a. An increase in airway eosinophils during acute exacerbations may be

important.

b. Despite the apparent absence of eosinophils in some studies, levels of ECPand EPO in induced sputum are elevated in COPD, suggesting that eosinophils may be

present but degranulated and therefore no longer recognizable by light microscopy.

c. The high levels of neutrophil elastase in COPD may be responsible for

eosinophil degranulation.

5. pithelial cells:

A. Airway and alveolar epithelial cells are likely to be important sources of

inflammatory mediators in COPD.

B. Cigarette smoke can activate epithelial cells to produce inflammatory mediators

such as TNF and IL-8.

C. The adhesion molecule E-selectin is unregulated on airway epithelial cells. This

molecule is involved in recruitment & adhesion of neutrophils.

Sites of Inflammatory Cell Increases in COPD

Large Airways Macrophages

T lymphocytes (especially CD8+)

Neutrophils (Severe disease only)

Eosinophils in some patients

Small Airways Macrophages

T lymphocytes (especially CD8+)

Eosinophils in some patients

Parenchyma Macrophages

T lymphocytes (especially CD8+)

Neutrophils

b) Inflammatory mediators

Many inflammatory mediators are involved in COPD, including: - LTB4, IL-8 & TNF-.However, little is currently known about the production and specific role of these mediators in

COPD.

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3. Macrophage inflammatory protein-1a (MIP-1a) is increase in the BAL of COPDpatients compared to normal subjects and healthy smokers, and also shows increased

expression in airway epithelial cells in COPD patients. It may contribute to

macrophage activation in COPD.

4. Granulocyte-macrophage colony stimulating factor (GM-CSF) increasedconcentrations in the BAL fluid of stable COPD patients and at markedly elevated

levels during exacerbations. The number ofGM-CSF-immunoreactive macrophagesis also increased in sputum of COPD patients. The substance is important for

neutrophil survival and may play a role in enhancing neutrophilic inflammation.

5. Transforming growth factor-b (TGF- and epidermal growth factor (EGF)showincreased expression in epithelial cells and submucosal cells (eosinophils and

fibroblasts) in COPD patients. These mediators may play a role in airway remodeling

in COPD

6. Endothelin-1 (ET-1), a potent VC, is found at increased concentrations in inducedsputum of COPD patients. Patients with severe COPD have elevated plasma levels of

ET-1, which is probably related to their chronic hypoxia. Finally, the pulmonary

endothelial cells of COPD patients and 2ry PH show increased expression of ET-1.,

suggesting that ET-1 may contribute to the vascular remodeling associated with

hypoxic pulmonary hypertension.

7. Neuropeptides such as substance P (SP), Calcitonin gene-related peptide, andvasoactive intestinal peptide (VIP), have potent effects on vascular function and mucus

secretion. An increased concentration of SP is found in sputum of patients with chronic

bronchitis.

8. Complement. Activation of the complement pathway via generation of the potentchemotaxin C5a may play a significant role in the neutrophil accumulation seen in the

lungs of patients with COPD.

Mechanisms of Lung Damage in COPD

1. Mechanisms of mucus hyper secretion: Mucus hyper secretion in COPD is caused by thestimulation of enlarged mucus secreting glands and increased number of goblet cells by

inflammatory mediators. including Leukotrienes, proteases, and neuropeptides

2. Mechanisms of airway narrowing and fibrosis:

A. The airway narrowing in COPD is a result of to several mechanisms, including edema of

the airway mucosa due to inflammation, the presence of excess mucus in the small airways

due to goblet cell metaplasia, fibrosis of the small airways, and loss of elastic recoil

B. The fibrosis that contributes to airway narrowing is probably a consequence of chronic

injury and repair of the airways.

C. Injury of the small airways, eitherdirectly by inhaled toxins such as cigarette smoke orindirectly by the action of inflammatory mediators, likely initiates repair processes. Theairway epithelium has considerable capacity to repair itself, and it is likely that the repair

processes can often restore both anatomic structure and airway function.

D. Narrowing, particularly of the small airways is believed to contribute to airflow

limitation primarily in moderate to severe COPD. These airways are characterized by the

accumulation of fibrotic connective tissue, and like scar tissues at other sites, it is likely

that this peribronchial fibrosis contracts and thus narrows the airways.E. This peribronchial fibrosis is characterized by the accumulation of mesenchymal cells

(fibroblasts and myofibroblasts) together with extracellular connective tissue matrix.

Several mediators including TGF- endothelin-1, IGF-1, fibronectin, PDGF, and others

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are involved drive the accumulation of these cells (fibroblasts and myofibroblasts) and of

the matrix. Moreover, that several cells including mononuclear phagocytes and epithelial

cells produce mediators that can drive this process.

Mechanisms of parenchymal destruction:

Inflammation leads to a variety of processes that damage lung parenchymal structures; chief

among these processes are disruption of the proteinase-antiproteinase balance in the lung andincreased oxidative stress.

(A) Proteinase-Antiproteinase Imbalance

- In COPD there is an imbalance between proteinases and endogenous anti-proteinases.

- The theory of the interplay is that this inflammatory process which includes alveolarmacrophages in some way releases neutrophil chemotactic factors known as (IL-8) causing

neutrophils to emigrate from the blood space into the airspace to release elastase. In normalcircumstances alpha-1-antitrypsin binds to the elastase and prevents it from binding to elastin.Smoking inactivate the alpha-1-antitrypsin at its active site and air space release more active

oxygen species in smokers, than in non smokers. This reduces the ability of alpha-1-

antitrypsin to bind to elastase allowing active elastase to bind to elastin

proteinase/Antiproteinase enlargement of the airspace that is seen in emphysema.

- Proteinase/Antiproteinase has several causes: - including inflammation, geneticfactors, and oxidative stress, and can also be induced directly by cigarette smoke. The concept

has also been expanded to include additional proteinases and antiproteinases, to include toxic

moieties other than proteinases, and to reflect the ability of the lung to repair after injury.

Proteinases may be increased orantiproteinases may be inhibited. There are severalmechanisms leading to both situations in COPD. P-Selectin, L-Selectin adhesions are important

for the transport of inflammatory cells in the systemic circulation

-1. 1- antitrypsin / 1-protease inhibitors:

A. Emphysema developed in the absence of 1- antitrypsindeficiency by:

a. An increase in the proteinase burden, due to either

the presence of increased numbers of inflammatory leucocytes in airspaces or the

release of excess protease from the leucocytes.

b. A functional deficiency of protease inhibitors.

c. Combination of 1 and 2.

d. An abnormality in repair process fro lung connectivetissue.

B. Mechanism: since 1-AT is the only major inhibitors ofneutrophils elastase in lower airways, the presence of increased number of neutrophils in the

lungs of subjects with 1-AT deficiency, attracted by increased release of chemotactic

factors from alveolar macrophages, may create an increased elastase burden in the presence

of an antiprotease deficiency. It appears that the development of emphysema and hence the

decrease of life expectancy in subjects with 1-AT deficiency, occur particularly in presence

of additional risk factors of smoking. However, there are some patients who can survive to

old age with relatively well- preserved lung function even if they smoke.

C. Few patients who have PiZZ phenotype and who smoked cansurvive beyond 60 years of age, therefore some individual with this deficiency do not

develop severe airway obstruction.

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2. Pathogenesis of emphysema in patients without 1-antitrypsin deficiency:

The pathogenesis of emphysema and also of small

air way disease is more complex in patients without 1-AT deficiency, the clearest

association is with cigarette smoking.

There are several possible mechanismswhere cigarette smoke can alter the elastase- antielastase balance in the lungs,

assuming that the neutrophils elastase and AAT are the major players of in the

protease antiprotease imbalance.

In addition the role of other proteolyticenzymes derived from cells other than neutrophils, as well as the effects of lung

antiproteases other than 1-AT has to be considered.

Finally there are additional effects onretardation of elastin re-synthesis by cigarette smoke.

Since only 15-20% of smokers develop COPD, thequestion of susceptibility has to be considered. There are several pathogenic variables in

the development of COPD which may be genetically determines, such factors includes:

a. Cellular response to tobacco.

b. Bronchial hyperreactivity.

c. Variations in neutrophils and macrophages protease activity.

d. Protease inhibitor function.

e. Lung matrix injury and repair.

The mechanisms for the development of pulmonaryemphysema in subjects' without 1-AT deficiency are:

a. Increased protease burden.

b. Decreased antiprotease function.

c. Decreased synthesis of elastin.

1. Increase protease burden:

There are several processes by which elastase burden could be increased in cigarette smokers:

A. Increased sequestration migration of neutrophils into lungs in smokers.

There is 10 fold increases in number of neutrophils in BAL in smokers, althoughmacrophages still the predominant cells.

In some smokers neutrophils become sequestered in pulmonary circulation due todecrease deformability of it decrease their ability to pass through pulmonary

capillaries. Once sequestered, the cells may act upon by cytokines to increase their

adhesion to the endothelium and can migrate into lungs along chemotactic factors

gradient.

Chemotactic activity in smoker lung:Nicotine itself is chemotactic. Chemotacticfactors itself may be released from bronchial epithelium. Evidence suggesting a

deficiency of a chemotactic factor inactivator in serum of patients with 1-AT

deficiency uncontrolled recruitment of neutrophils to the airspaces in these patients

(similar mechanism may play a role inpatients without 1-AT deficiency).

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There is also evidence that circulating neutrophils are sensitized to chemotacticsignals, and neutrophils from COPD patients may show enhanced response tochemotactic agents.

B. Neutrophils from susceptible smoker may contain increased amount of elastasecompared with non-susceptible smokers.

Neutrophils elastase: there is an association between neutrophils elastase andairflow obstruction in patients with 1-AT deficiency. It may appear that those subjects

with COPD have neutrophils that, when activated release more elastase (controversy).

Some study show that immunoreactive leucocytes elastase concentrations in serum of

patients with COPD is doubled (this finding is true also in other chest diseases).

Enzymes other than neutrophils elastase have identified in the lungs, including:

a. Cathepsin G (relatively weak electrolytic enzyme but can actsynergistically with neutrophils elastase to degrade elastin)

b. Protease 3 (it is more potent at degrading elastin than neutrophils elastasein acid PH (7.5), but is less potent as neutral PH), it is also bactericidal. Its role in

development of emphysema is not yet identified.

c. Macrophages also produce Cathepsin L and which also degrade elastin atacidic PH.

However, studies failed to identify a role for these other elastolytic enzymes in pathogenesis of

emphysema.

C. Neutrophils, once recruited, may show enhance degranulation, leading to moreconnective tissue injury.

There is evidence ofincreased metalloproteinase, and four fold increase inmacrophages in BAL in smoker's cytokines neutrophils activation and

degranulation, and can also ingest and later release neutrophils elastase.

2. Decreased antiprotease functions:

1. Functional deficiency of 1-AT in the airspaces produces by smoking due to

oxidation of the methionine-358 residue at the active site of the 1-AT molecule. This can

occur by a direct oxidative effects cigarette or by oxidant released from activated airspace

leucocytes.

2. In addition, both macrophages and neutrophils from cigarette smokers release more

ROS than cells from non-smokers.

3. However, measurements of 1-AT in BAL from cigarette indicate that it remains

active in smokers.

Studies in elastase/ antielastase imbalance in BAL have failed to produce clear

supportive evidence in human for the protease/ antiprotease theory; in particular there is no

strong evidence for an imbalance between elastase and 1-AT in cigarette smokers. Several

explanations have been proffered to explain this unclear picture:

a. Other antiproteases may

contribute to the antiprotease shield in the lungs, in addition to 1-AT.

b. More subtle mechanisms may

reduce the inhibitory activity of1-AT.

c. The protease- antiprotease

imbalance occurs in micro-environment or lung interstitium, which is not sampled by

BAL.

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Other antiproteases:There is controversy regarding the role of other antiproteases in the pathogenesis of emphysema

due to: different techniques used to assess it. Several antiproteases inhibit the same enzymes.

This led to the suggestion by some workers that 1-AT is responsible for less than 50% of

inhibition neutrophils elastase in BAL, whereas other found it to b responsible for 90% of

elastolytic activity.1. Antileucoprotease (ALP):

Non-glycosylated protein present in lungs and a variety of other body secretions.It present in mucus including, nose, lung, and reproductive tract.

It is an important reversible inhibitor of several serine proteases.

Sites in the lungs:

1. It present in high concentrations in bronchial secretion where it exceeds that of1-

AT, it has been localized at non-ciliated cells of the epithelium and the serous cells

of the submucosal gland

2. It also present in Clara cells and peripheral airways, although at lesser concentrations

than in 1-AT, it identified at the Clara and Goblet cells.

3. Immunochemical quantification of ALP relative to AAT shows that: intracheobronchial tree the concentration of ALP is 3 times greater than 1-AT. In

peripheral airspaces the ALP/ 1-AT molar ratio is approximately 0.1. This suggests

that ALP is the major inhibitors of neutrophils elastase in the large airways.

4. Immunohistological techniques indicate that ALP is presenting in the alveolar wallof human lungs, especially localized in association with elastin fibers. Thus although

there is lower concentration of ALP than 1-AT in peripheral airspace, its

localization in association with elastin more effective than 1-AT at inhibiting

neutrophils elastase already bound to elastin limit connective tissue destruction

by adherent neutrophils more effective in vivo at inhibiting elastase locally in lung

tissue. This is in contrast to 1-AT which inhibits elastase in solutions.

Although these Immunohistological studies suggest that ALP is important

inhibitors of neutrophils elastase, there is no evidence of quantities, functional, or absolute

deficiency of ALP in emphysema.

2. Elastase specific inhibitors called elafin:

3. Low-affinity inhibitor of neutrophils elastase similar to ALP has beendemonstrated.

4. Metalloproteinase inhibitors and cysteine protease inhibitors.

Other mechanisms that reduces the effectivenessof antiproteases:

Additional mechanisms that of AAT include:

1. Cleavage of active site and complex formation with the enzyme. Both of these

mechanisms produce a change in the molecular size of1-AT.

2. Other changes that can occur in the activity of AAT in smokers such as a reduction in the

association rate constant of1-AT from BAL for neutrophils elastase. S

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3. recent studies have shown a polymorphism of the 1-AT gene, which is due to a single

change in nucleotide sequence of the gene alter the recognition sequence for

restriction enzyme Iaq1 failure of the enzyme to cleave DNA at this site. The areainvolved in this polymorphism is the enhancer sequences that can amplify gene

expression susceptible smokers do not increase their1-AT levels during the acute

phase response to infection.

Protease-antiprotease imbalance in amicroenvironment in the lungs:

1. This is thought to result from tight cell adherence to connective tissue substrates and

release of the enzyme at interface between the two, thus excluding the surrounding

inhibitors.

2. thus the neutrophils has the potential to degrade elastin in a micro-environment, during

migration through interstitium, or in the airspaces

3. It has been suggested that the proteolytic imbalance responsible for may even be derived

from the neutrophils delayed in the microvasculature by cigarette smoke. Theseneutrophils may be triggered to release ROS inactivate 1-AT proteolytic enzyme

to diffuse the short distance from the neutrophil to elastin and collagen in the alveolar

wall.

4. This increased oxidant stress in the intravascular space increase the sequestration and

adhesion neutrophils in the pulmonary microvasculature and also enhance the

inactivation of1-AT.

5. Some supports for this hypothesis come from:

- Marked decrease in the antioxidant capacity of the plasma that occurs during

acute cigarette smoke.

- Studies which show that neutrophils have the ability to degrade connective tissue

matrices even in the presence of active enzyme inhibitors.

Decreased synthesis of elastin

1. Immunologically reactive elastase, which can be measured in plasma and BAL fluid, is

usually in an inactive form complexed with the inhibitors.

2. Measurements of the elastin degradation products: is usually used as a reflection ofthe excess proteolytic activity which is thought to occur in emphysema.

3. The conc. of the elastin cross-linking enzyme desmosine and elastin peptides are;

a. Elevated in smokers and patients with COPD.

b. The impact of this finding is diminished by the fact that it is not specific

for elastin degradation in the lungs, especially as the turn over of lung elastin is

likely to be very low.

c. In fact there is a high background level of excretion of desmosine in

normal non-smokers mask small changes that may occur in smokers, thus

there is no difference in urinary desmosine in normal adults or those with 1-AT

deficiency or emphysema. (Controversy).

d. Study demonstrated that urinary desmosine levels Is higher in those

smokers with a rapid decline in FEV1.

Fibrinogen degradation product:

- Measured as an assessment of the activity of the released elastase.

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- Although early studies demonstrated that this peptide may be elevated in smokers

and patients with 1-AT, there is still doubt over the suitability of this degradation

products as a marker of elastase activity since the peptide is very labile and

degraded rapidly

4. It has been suggested that a further factor which may lead to the development of

emphysema is a defect in elastin re-synthesis. Lysyl oxidase is an enzyme required forthe cross-linking formation of normal tissue elastin:

A. Emphysema is described in condition characterized by deficiency of it (cutis

laxa).

B. Lathyrogens, which prevent elastin-cross linking, can be used to produce

experimental emphysema.

C. Some evidence suggests that lysyl oxidase activity is reduced by cigarette

smoking preventing elastin repair emphysema.

Imbalance between Proteases and Antiproteases in COPD

6. Oxidative Stress .

1. There is evidence for increased oxidative stress in COPD patients

2. Oxidants such as super oxide anion, nitric oxide, hydroxyl radical peroxide (H2O2), and

peroxy nitrite are abundant in cigarette smoke. The concentration of oxidants may be as

high as 1017/puffs.

3. Oxidants may cause direct tissue damage or augment the inflammatory process indirectly

through oxidative inactivation of neutrophils.

4. Activated macrophages and neutrophils also serve as an endogenous source for oxidants

such as H2O2 and O2.

5. The effects of smoking on the Oxidant / /anti Oxidant balance or elastase inhibitors suchas 1-AT:

Inactivation of proteinase inhibitor.

The relationship of Oxidant / anti Oxidant balance to systemic Oxidant stress

Oxidant / anti Oxidant imbalance in airspace epithelium and the injury that cigarette

smoking may cause

The relationship of gene activation to cigarette smoke and other oxidant (The Meaning of life)is the compound glutathione that is an extremely important cellular antioxidant, particularly in

the lungs. Its levels are related to good health, and its concentrations decreases with age.

1. It is part of the glutathione redox system which uses the enzyme glutathione

peroxidase to detoxify lipid peroxides and hydrogen peroxide.

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2. Glutathione is concentrated in the epithelial lining fluid at a much higher level than

in the plasma.

3. In chronic smokers there is almost a doubling of glutathione in the epithelial lining

fluid compared with non smokers But an hour after cigarette is actually smoked, no

increase in glutathione can be de detected.

a. Mechanisms of vascular damage:

1. The association between pulmonary hypertension and COPD is well documented.

2. Three factors may contribute to the increase PAP: vasoconstriction,thickening of thevessel wall, and reduction of the capillary bed by emphysema.

A. In advanced COPD, hypoxemia has a predominant role in determining the increase

PAP. The hypoxic stimulus produces VC of pulmonary arteries and promotes the

remodeling of the vessel wall, either by inducing the release ofgrowth factors or as aconsequence of the mechanical stress that result from hypoxic vasoconstriction.

B. At the initial stages of COPD, when patients are not hypoxemic, other factors might

operate. Endothelial dysfunction of pulmonary arteries occurs early in COPD. Sinceendothelium plays an important role in regulating vascular tone and cell proliferation,

it is likely that a direct effect of cigarette smoke products on endothelial cells or

inflammatory mediators might initiate the sequence of events that result ultimately in

vascular damage.

PATHOPHYSIOLOGY

Integrated effects of COPD on breathing

Airway inflammation Bronchospasm

Loss of recoil airway narrowing abnormal gas exchange

Hyper inflation

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Diaphragm Weakness Respiratory muscle Accessory respiratory muscles

Disintegration

Increased respiratory load

Respiratory muscle fatigue

Dyspnea

Increased ventilatory drive

PATHOPHYSIOLOGY

Pathological changes in COPD lead to corresponding physiological abnormalities characteristic

of COPD that usually become evident first during exercise and later all the time. Thesephysiological changes include:-

1. Mucus hypersecretion and ciliary dysfunction

2. Chronic airflow limitation which alter pulmonary mechanics

3. Gas exchange abnormalities

4. Pulmonary hypertension and cor pulmonale , usually developing in this order over the

course of the disease.

1. Mucus hypersecretion and ciliary dysfunction resulting in ch. cough & sputumproduction

Sputum production represents the clearance of a mucoid inflammatory exudates from the

lumen of the bronchi. This exudate is formed from the microvessels of the bronchialcirculation and containsplasma proteins, inflammatory cells and small amounts of mucusadded from goblet cells on the surface epithelium and the e