Respiratory Module

Pathology 1

Hashemite University Faculty Of Medicine Second year students

Module of Respiratory System

Pathology : Total 9 Lectures Lectures prepared By : Dr.Ghada Nazar Aljussani MBCHB.,FRCPath UKIRAqi Board in pathology Jordanian Board in pathology European Board in pathology

Respiratory System ObjectivesPart IObstructive pulmonary diseases Acute Respiratory distress Syndrome Pneumoconiosis(occupational lung diseases) SarcoidosisAtelectasis (lung collapse) Pulmonary hypertension Good Pasture syndrome .Reference : Robbin’s Basic Pathology . Kumar ,ABBAS ,Aster. 10th edition .

Obstructive pulmonary diseasesObstructive Pulmonary Diseases* Characterized by limitation of airflow usually resulting from an

increase in resistance caused by partial or complete obstruction of bronchial tree at any level .*The major obstructive disorders are : Chronic BronchitisBronchiectasis AsthmaEmphysema.

ChronicBronchitis :Definition :A clinical condition characterized by a persistent productive cough forat least three consecutive months in at least two consecutive years .(WHO)It is common among cigarette smokers and urban dwellers in smog -ridden cities. (mixture of smock ,fog and chemical fumes)20% -25% of men between age groups of 40-65 years are mostly affected .

Chronic bronchitis can occur in several forms :1 Simple chronic bronchitis :Most patients with simple chronic bronchitis have a productive cough with mucoid sputum but airflow is not obstructed.2 Chronic asthmatic bronchitis :Some patients with chronic bronchitis may demonstrate hyper-responsive airways with intermittent bronchospasm and wheezing .3 Chronic obstructive bronchitis :Including heavy smokers who develop frank chronic outflow obstruction usually with associated emphysema .

Chronic bronchitisFeatures include :

-Cough continuous 3 months / 2 years

productive of sputum may persists indefinitely without ventilator dysfunction.

Pathology :bronchial lumen. Increase mucus in

Increase number of mucus glands (Reid Index) Increased intra epithelial goblet cells .Squamous metaplasia .

Pathogenesis : The destructive feature of chronic bronchitis is hyper secretion of

mucus , beginning in the large airways as trachea or major bronchi .In advanced disease even small bronchioles are involved .

Although the most important cause is cigarette smoking other air pollutants such as sulfur dioxide & nitrogen oxide may contribute . These environmental irritants induce hypertrophy of mucus glands in

the trachea & main stem bronchi & goblet cell metaplasia lead to a marked increase in mucus-secreting goblet cells replacing the ciliated epithelial cells in the surface epithelium of smaller bronchi & bronchioles .

In addition these irritants cause inflammation with infiltration of CD-8 T lymphocytes , macrophages & neutrophils .

It is postulated that many of the respiratory effects ofenvironmental irritants i.e. mucosal hyper secretion aremediated by local release of T-cell cytokines such as IL-13

the transcription of mucin gene & neutrophil elastaseMU5AC which is increased as a consequence of exposureto tobacco smoke in both in vitro & in vivo experimental modelsare in part mediated by signaling via the epidermal growth

factor receptor pathways. Microbial infection is oftenpresent but has a secondary role chiefly by maintaining theinflammation and exacerbating symptoms .

Because of reduced ciliary movement the mucus cannot becoughed out & since the stagnated mucus is a good medium forbacterial growth , secondary bacterial infection developsfrequently leading to inflammation, ulceration of bronchial mucosafollowed by fibrosis & scarring causing chronic obstructive

pulmonary disease. (COPD). The morphological basis of theadvanced chronic bronchitis is more peripheral and results from :1So called small-airways disease induced by goblet-cell

metaplasia with mucus-plugging of bronchiolar lumeninflammation and fibrosis.2 Co-existent emphysema:It is generally believed that while small airways disease also knownas chronic bronchiolitis is an important component , chronicbronchitis with a significant airflow obstruction is almost alwayscomplicated by emphysema.

Morphology:

Grossly:

The mucosal lining of larger airways is usually hyperemic & swollen by edema fluid. It is often covered by a layer of mucinous ormucopurulent secretion.The smaller bronchi & bronchioles may also be filled with similar secretions.

Histologically:The diagnostic feature of chronic bronchitis in the trachea and larger

hyperplasia of submucosal mucus-secreting glands .bronchi is goblet cell metaplasia of bronchial epithelium and

Themagnitude of the increase in size is assessed by the ratio of thethickness of the submucosal gland layer to that of the bronchial wallfrom epithelial layer down to cartilage . this ratio is called Reid index

normally is (0.4) . In chronic bronchitis it equals unityi.e. (1/1).

Figure 2 : Gross view of trachea and major bronchi

in chronic bronchitis , looking hyperemic & swollen

mucosa

Figure 3 : Gross view of chronic bronchitis showing

inflamed hyperemic bronchial mucosa with thick

purulent secretion filling the lumen.

Figure 4 : Gross appearance of lung tissue in chronic

bronchitis, dilated bronchi filled brownish mucoid

secretion .

Figure 5 : Microscopic view of normal bronchus .

Figure 6 : Measuring Reid index ,normal ¼ in chronic

bronchitis it is increased may be 1/1 .

A variable density of inflammatory cells largely mononuclearcells but sometimes with neutrophils is frequently present inbronchial mucosa, their number may be increased during

exacerbations. Chronic

are devoidbronchiolitis is

ofinflammatoryinflammationsubmucosal glands & cartilage

of small bronchioles, whichshow goblet cell

metaplasia, mucus plugging inflammation & fibrosis.In sever cases narrowing and obstruction with completeobliteration of the lumen due to fibrosis called bronchiolitis

Obliterans.

Figure 7 : Microscopic view of bronchial mucosa .Left : Normal ,

ciliated pseudostratified columnar epithelium . Right : chronic

bronchitis showing goblet cell metaplasia replacing the ciliated

epithelium .

Figure 8 : Microscopic view showing goblet cell metaplasia (right )

of bronchiolar epithelium (left) with inflammatory cells infiltrate in

surrounding tissue .

Figure 9 : Microscopic view of bronchial mucosa showing

goblet cell metaplasia , there is complete replacement of the

ciliated respiratory epithelium by goblet cells .

Figure 10 : Microscopic view of bronchial mucosa in chronic

bronchitis showing marked submucosal gland hyperplasia (arrow).

Figure 11: Microscopic view of chronic bronchitis,

showing florid mucous glands hyperplasia .

Figure 12 : Microscopic view of chronic bronchitis,

showing per bronchial inflammation and fibrosis .

Figure 13 : Microscopic view of chronic bronchitis , showing dense

inflammatory infiltrate in peri bronchial tissue & thick purulent material in

the lumen .

Clinical course :

Patients with chronic bronchitis complain of

prominent cough with the production of excessive

mucoid or mucopurulent sputum which may persistsindefinitely without ventilator dysfunction. Somepatients may develop chronic obstructive pulmonary disease (

COPD) with outflow obstruction , this is accompanied byhypercapnia, hypoxemia & in sever cases cyanosis (blue

bloater ), such conditions may be associated withemphysema. With progression chronic bronchitis maycomplicate by pulmonary hypertension & cardiac failure.

Recurrent infections & respiratory failure are constantthreat. Squamous metaplasia of epithelium ,with dysplasiamay complicate to squamous cell carcinoma of bronchus.

Figure 14: Microscopic view of bronchial mucosa showing

squamous metaplasia of respiratory epithelium.

Asthma

Definition :Is a chronic inflammatory disorder of the airways that causesrecurrent episodes of wheezing, breathlessness, chest

tightness and cough, particularly at night & / orearly in the morning. This clinical picture is caused by

repeated immediate hypersensitivity and late phasereactions in the lungs that gives rise to the triad ofintermittent and reversible airway obstruction , chronicbronchial inflammation with eosinophils and bronchialsmooth muscle hypertrophy and hyper reactivity.

Asthma is a heterogeneous disease triggered by a variety of inciting agents.Two types of asthma has been identified :

Extrinsic asthma :

Constitutes 70% of cases , called atopic due to IgE & TH2 lymphocytes -mediated immune response to environmentalantigens.

Intrinsic asthma :Constitutes 30% of cases or non-atopic and is triggered bynonimmune stimuli such as drugs like aspirin , penicillin,

pulmonary infections especially viral, cold,

psychological stress, exercise & inhaled irritants.

Atopic Asthma :

The most common type of asthma, usually begins in

childhood with a positive history of atopy, in

genetically predisposed individuals. Asthmatic attacks

are preceded by allergic rhinitis, urticarial, skin rash, or

eczema. The disease is triggered by environmental

antigens such as dust, pollens, animal dandruff and

foods. A skin test is positive when the offending

antigen is injected to the skin of the patient , this

results in an immediate wheal and flare reaction

caused by Type I, IgE - mediated hypersensitivity

reaction, it appears within 24 hours .

Figure 15: Skin test. Positive in individuals

with atopic asthma.

Pathogenesis :

The major etiologic factor in asthma is geneticpredisposition to type I hypersensitivity (atopy).

In the airways sensitization is induced by the inhaledallergen stimulate the helper T lymphocytes ( TH 2 )cells which release interleukins IL-4 & IL-5 lead to thesynthesis of IgE that bind to the submucosal mastcells which play an important role in thepathogenesis of asthma followed by acute & chronicairway inflammation and bronchospasm caused byconstriction of bronchial smooth muscle.

Pathogenesis o f atopic asthma can be summarized into four stages as follows:

1- Stage of sensitization :

Exposure to the inhaled inciting

(allergen) which will be attached to

antigen

allergen-

presenting cells (APC) called dendritic cells on

the surface of bronchial epithelium, this will lead

to activation of Helper T lymphocytes (TH2).

These cells will release (1) IL-4 that stimulates

plasma cells to produce IgE antibody which is

going to be attached to receptors on mast cell

membrane.

(2) IL-5 that is chemotactic to & activating

eosinophils, which will accumulate in the mucosa

and produce major basic protein or eosinophil

cationic protein both are toxic to epithelial cells

can induce their damage leading to opening of

gap junctions between them , this helps the

allergen to enter to bronchial mucosa to activate

more TH2 lymphocytes & mast cells already

present within bronchial mucosa. (3) IL-13 that

stimulates mucus production from goblet cells

and the submucosal glands.

Figure 16: Diagrammatic presentation of pathogenesis

of atopic asthma , initial stage of sensitization .

2- Stage of immediate –phase hypersensitivity

reaction :Starts immediately or within minutes after repeated exposure

to the same antigen characterized by increased

permeability and edema fluid accumulating in

mucosa with smooth muscle spasm causing

vascular

bronchial

broncho

constriction, the patient will have sever dyspnoea wheezing &

difficulty of expiration being evident within 5-30 minutes

following the second exposure to the same antigen and

subsides by 60 minutes. In this phase the reaction will be

triggered by antigen-induced cross linking of IgE antibodies

on mast cells in the airways leading to the release of their

granules .

Which are the mediators including Histamine,

eosinophil chemotactic factor (ECF), Leukotriens

B4 ,C4 ,D4 & E4. Platelets activating factor (PAF),

prostaglandins & thromboxane. These will induce

increased vascular permeability, edema more

eosinophils & neutrophils accumulation together

with bronchoconstriction. In addition ,stimulation

of subepithelial vagal (parasympathetic) receptors

as well as acetylcholine released

provoke

from

reflexintrapulmonary motor nerves

bronchoconstriction.

Figure 17 : Activation of mast cell by IgE .

3- Stage of Late phase reaction :

Starts 4-8 hours later and may persist for 12-24 hours.

In this phase eosinophils are particularly important in

addition to the major basic protein & eosinophil cationic

protein which cause epithelial cell damage, they also

peroxidaseproduce eosinophil

damage , and release mediators

that cause tissue

like

which causes bronchoconstriction. This phase

leukotriens C4

is

characterized by inflammation ,tissue destruction,

ulceration, smooth muscle spasm well asmucosal

increased inflammatory cells infiltration including

eosinophils, neutrophils & lymphocytes within mucosa ,

being induced by mediators like cytokines(IL-1) ,tumor

necrosis factor (TNF) & leukotrien B4 .

Figure 18: Diagrammatic view of IgE- mediated mast

cells reaction

4- Stage of Airway outflow remodeling :

This refers to the structural changes in the

bronchial wall occurring as a late secondary

deposition ofchange in asthma, including

collagen in the subepithelial

membrane, increased mucus

basement

production

together with hypertrophy of bronchial smooth

muscle and fibroblasts this have been attributed

to inherited predisposition associated with

polymorphism in gene called ADAM 33 which is

implicated in smooth muscle & fibroblast

proliferation.

Figure 19 : Comparison between normal bronchial wall

(top) & asthmatic bronchus (bottom).

Figure 20: Microscopic view ,showing normal compared to asthmatic

bronchitis (right) showing mucus hyperplasia of epithelium , thickening of

basement membrane & smooth muscle hypertrophy .

Figure 21: Microscopic view of asthmatic bronchitis showing

mucous metaplasia & thickened basement membrane .

Non-atopic asthma :The mechanism of bronchial inflammation and hyper responsivenessis less clear in this type. Viral infection & inhalation of irritant

pollutants as sulfur dioxide & nitrogen oxide, have beenincriminated. A positive family history is uncommon serum Ig E levelis normal . Skin test is negative. The ultimate mediators of airwayobstruction & eosinophilia are common .Drug-induced asthma :

Aspirin is the most common cause of asthma in aspirin sensitive patients. The precise mechanism is unknown, possibly related to theeffect of aspirin which inhibits cyclo-oxygenase pathway of arachidonic acid metabolism by shifting it towards lipoxygenasepathway resulting in production of the bronchonstrictor leukotriens .

Occupational asthma, Fumes, resins & plastics organicor chemical dust of ( wood, cotton, platinum ) gases

as toluene, exposure to such products induce asthmaticattacks in sensitive individuals.

Morphology :

Grossly :

In fatal cases with status asthmaticus or cases of

prolonged chronic asthma , the lungs look over

distended because of the over inflation there may

be also presents areas of atelectasis. The most

striking gross finding is occlusion of the bronchi &

bronchioles by thick mucus plugs .

Histologically :

The sputum of patient as well as in tissue sections

of bronchi show the mucus plugs contain whorls of

shed necrotic epithelial cells called (Curschmann’s

spiral). Also, seen

charcot-leyden crystals which are made up

are numerous eosinophils &

of

eosinophilic protein. Features of airway remodeling

including thickening of basement membrane of

bronchial epithelium by dense collagen deposition,

with edema & inflammatory infiltrate in which

eosinophils & mast cells predominate . Also present

increase in size of submucosal glands &

hypertrophy of bronchial muscle wall.

Figure 22: Charcot –leyden crystal seen in sputum of asthmatic

patient, consisting of eosinophils - derived crystalline protein .

Figure 23 : Curschman’s spirals seen in sputum of

asthmatic patients .

Clinically: The attack of asthma is characterized by sever

dyspnoea, the chief difficulty is during expiration , with

wheezing & cough. The patient can get air into the lungs but

cannot get it out, this leads to progressive over inflation of the

lungs & air is trapped distal to the bronchi which are

obstructed by mucus plugs & are constricted.The attack lasts

from one minute to several hours then gradually subsides

spontaneously or with therapy with interval between attacks

are free from symptoms. Occasionally severe paroxysms

occur that does not respond to therapy (like broncho-dilators

& steroids ) & persists for days this is called Status

asthmaticus . There is associated hypercapnoea increased

PaCO2 acidosis & sever hypoxia, but such attacks may be

fatal .

Bronchiectasis

Definition :

Is a permanent

bronchioles, caused by destruction

dilatation of bronchi &

of

muscle & elastic supporting tissue , resulting

from or associated with chronic necrotizing

infections. It is not a primary disease, but

rather a secondary sequel to persistent

infections or obstruction caused by a variety

of conditions

Etiology:

There are numerous predisposing disorders including:1Bronchial obstruction: caused by tumor, foreign body or by impaction by mucus. In such conditions thebronchiectasis tends to be confined to the obstructed lung segment.2 Bronchial asthma

3 Chronic bronchitis

4Congenital bronchiectasis: as in cystic

fibrosis which leads to a widespread bronchiectasisresulting from bronchial obstruction and infectioncaused by secretion of an abnormal viscid

mucus.

5Immune deficiency states: particularly immunoglobulin deficiency. Bronchiectasis developsdue to an increased susceptibility to repeatedbacterial infections.

6- Localised & diffuse bronchiectasis, can occur inKartegner’s syndrome which is an autosomal recessivedisorder, is frequently associated with bronchiectasis andsterility in males .Structural abnormalities of the cilia

impair muco-ciliary clearance in the airways leading topersistent infections , and reduce mobility of the spermatozoa.7- Necrotizing or suppurative pneumonias: caused bystaphylococcus aureus, Klebsiella spp, in children

cough &pneumonia complicating measles, whooping

influenza.

8- Tuberculous broncho-pneumonia.

Pathogenesis :

Two critical processes are involved:

Bronchial obstruction.

Chronic persistent infections.

In any cause of obstruction interference with theclearance mechanisms lead to secondary infectionsthat result in necrosis and weakening of thebronchial supporting tissues as the muscle coat andelastic tissue infections also involve the perbronchial tissue with fibrosis that cause traction ofthe bronchial walls towards the pleura andsurrounding connective tissues.

Morphology :

Grossly :

Bronchi of the lower lobes of both lungs are

frequently involved by bronchiectasis, they

become markedly dilated 4-5 times their normal

diameter, particularly the most vertical ones due

to gravitational accumulation of secretions ,they

can be followed towards the pleura , may look

cylindrical or cystic in appearance. Their Lumina

are filled with a dirty purulent exudates when

removed a reddish ulcerated mucosa seen.

Figure 24 : Gross appearance of lung in bronchiectasis (cylindrical

form ) markedly dilated bronchi reaching pleural surface .

Figure 25: Gross appearance of the lung showing cystic

bronchiectasis.

Figure 26: Gross appearance of lung showing bronchiectasis,

dilated bronchi filled with thick foul smelling secretions.

Microscopically :The histological changes vary with the severity andduration of the disease. In an active full-blown diseasean intense acute & chronic inflammatory exudateswithin the wall of the bronchi & bronchioles seen anddesquamation of lining epithelium cause extensiveulceration. In severe cases abnormal dilatation occursdue to necrosis & fibrosis of muscle coat with associatedper bronchial fibrosis. In severe cases lung abscesses

may develop.

Figure 27: Microscopic view of bronchiectasis , showing dense

chronic inflammatory cells infiltration and fibrosis of bronchial

wall.

Figure 28: Microscopic view of chronic advanced bronchiectasis

Clinical features :

The patient presents with sever persistent cough

with expectoration of a muco-purulent fowl-smelling

sputum which may contain flecks of blood, frank

hemoptysis may occur. Patients may present with

clubbing of fingers. In severe bronchiectasis

significant obstructive ventilator defects develop

including hypoxemia, hypercapnia, pulmonary

hypertension and cor pulmonale. Septic emboli may

arise from lung abscess may lead to brain abscess.

Amyloidosis can arise is severe prolongedbronchiectasis.

Complications of bronchiectasis :

1- Hypoxia, hypercapnia.

2 Hemoptysis.

3 Clubbing of fingers.

4Septic embolism (brain & splenic abscesses).

5- Amyloidosis.

6 Respiratory failure.

7 lung abscess.

8 Cor pulmonale .

9 Pulmonary hypertension.

Figure 29: Gross view of liver in amyloidosis .

Figure 30: Microscopic view of advanced amyloidosis in the

liver.

Figure 31 : Clubbing of fingers in patient with advanced

bronchiectasis .

Emphysema:Is characterized by abnormal permanent

enlargement of the airspaces distal to

the terminal bronchioles, accompaniedby destruction of their walls without

obvious fibrosis.

Figure 32: Gross appearance of emphysematous

lungs. Both lungs are over inflated covering the

heart .

Anatomic description:The main bronchi giving rise to progressivelysmaller airways called bronchioles, which aredistinguished from bronchi by lacking cartilage &

submucosal glands in their walls. Additionalbranching of the bronchioles lead to terminal

bronchioles, the part of the lung distal toterminal bronchiole is called acinus.

The pulmonary acini are composed of respiratory

bronchioles (emanating from terminal bronchioles ) that proceed into alveolar ducts which immediately branch into alveolar sac ,

the blind ends of the respiratory passages whose walls are formed entirely of alveoli, the ultimate site for gas exchange. A cluster of

3-5 acini is called a lobule. The alveolar wall consists entirely of capillary endothelium, basement membrane, and surrounding interstitial tissue separating the endothelium from the alveolar lining epithelium. The interstitial tissue, composed of fine elastic tissue, collage & fibroblast-like cells, smooth muscle cells, mast cells and few mononuclear cells .

The alveolar septa consists of continuouslayer of two types of cells. A flattened plate-like Type I pneumocytes, covering 95%

of alveolar surface, and rounded Type II

pneumocytes, which are source ofpulmonary surfactant and the main cellsinvolved in repair of pulmonary

epithelium.

Figure 33: Diagrammatic view of lung anatomy.

Figure 34: Alveolar acinus in the lung.

Types of emphysema :

Emphysema can be classified according to the anatomic distribution within the lobule .The four major types of emphysema are : 1- Centrilobular Emphysema.2 Panacinar Emphysema.3Distal acinar Emphysema. (Paraseptal E.) 4- Irregular Emphysema .Only the first two are clinically significant airwayobstruction , with centriacinar E. being 20-folds

more common than panacinar type.

Centri-acinar Emphysema :In this type of emphysema the central or the proximal part

of the acini , formed by the respiratory bronchioles are affected , while the distal alveoli are spared . Thus both

normal & emphysematous air spaces exist within the same acinus & lobule .The lesions are more common & sever in the upper lobes

particularly in the apical segments .In sever cases even the distal acinus becomes involved , thendifferentiation from pan-acinar E . becomes difficult.This type of E. is most commonly seen as a consequence of

cigarette smoking in people who donot have congenital deficiency of alfa 1 antitrypsin enzyme .It is 20-folds commoner than centri-acinar E.

Figure 40 : Gross appearance of lung with centriacinar emphysema

with black color due to carbon particles ,common among smokers &

coal mine workers .

(Figure 41 : Gross appearance of centriacinar emphysema showing

centrilobular dilatation surrounded by normal lung tissue .

Pan-acinar Emphysema :In this type of E. the acini are uniformly

enlarged from the level of the respiratory

bronchioles to the terminal blind alveoli .In contrast to centri-acinar E. it tends to

occur in the lower lung zones and is the

type

of E. that occurs in alfa 1 anti-trypsin

deficiency.

Figure 42 : Gross view of lung showing panacinar emphysema

Figure 43 : Gross view of panacinar emphysemaFigure 43 : Gross view of panacinar emphysema

Distal acinar Emphysema :Or paraseptal E.

In this form of E. , the proximal portion of

the acinus is normal , but the distal part is

primarily involved .The emphysema is more striking adjacent to the pleura along the lobular connective tissuesepta , and at the margin of the lobule .

It occurs adjacent to areas of fibrosis ,

scarring or atelactasis, and is more severe in

the upper half of the lungs.

Figure 44 : Distal acinar or paraseptal emphysema .

Paraseptal emphysema

Paraseptal & centriacinar emphysema

Irregular bulous emphysema .

The characteristic findings are the presence of multiple contiguous air-spaces that range from 0.5-2 cm. in diameter, sometimes forming a cyst-like spacescalled Bullae ,when ruptures is the most common cause ofspontenuous pneumothorax in young patients .

Irregular Emphysema

In this type the acinus is irregularly involved , it is associated with scarring In a healed inflammatory diseases.Although clinically asymptomatic, it is the most common form ofemphysema.

Irregular emphysema .

Gross view of lung showing irregular emphysema dilated

alveoli occurring at site of scarring at the apex of upper lobe .

Gross view of lung showing irregular emphysema

, dilatation seen near scarred & fibrotic lung tissue .

Pathogenesis :The recent theory regarding the pathogenesis of emphysemafavors a critical imbalances , the protease-anti protease

imbalance and the oxidase –

anti oxidase imbalance , such imbalances almost always coexist .The protease-anti protease imbalance hypothesisis based on the observation that patients withgenetic deficiency of anti-protease alfa 1 antitrypsin

have a marked increased tendency to develop pulmonary emphysema .

Liver biopsy in alfa 1 antitrypsin deficiency ,showing purple granules in

hepatocytes (arrows) .

Alfa 1 antitrypsin normally present in serum,tissue fluids & macrophages ,is a major inhibitor of protease particularly elastase which is secreted by neutrophils during inflammation . Alfa-1 antitrypsin is encoded by a gene on the proteinase inhibitor Pi -locus on chromosome 14, present as M allele , and Z allele .

Most people who are homozygous for Z allele (ZZ),have marked decrease in alfa 1 antitrypsin.Exposure to toxic agents such as tobacco or pollutants induce ongoing inflammation with infiltration of neutrophils , macrophages & lymphocytes in lung tissue .

Elastases , cytokines like IL-8 & oxidants are released by

these cells ,causing epithelial injury and proteolysis of the

Unless inhibited by )extracellular matrix (ECM) antitrypsin)

anti-elastase

and antioxidants , the cycle of inflammation & protelysis of

ECM continues .

More than 80% of patients with congenital α 1

antitrypsin deficiency develop symptomaticemphysema.

There is marked individual variation in susceptibility to

develop emphysema / Chronic obstructive pulmonary

diseases (COPD) .

Multiple genetic factors control the response to injury after smoking .

The transforming growth factor β (TGF β ) gene exhibits

polymorphisms that influence susceptibility to the development of

COPD by influencing the

response of the mesenchymal cells to injury .

With certain polymorphisms , mesenchymal cells response

to TGF β signaling is reduced result in an inadequate repair

of elastin injury caused by inhaled

toxins .

In addition to elastase , matrix metallo proteases MMP derived from macrophages & neutrophils have a role in tissue destruction . Especially MMP9 &MMP12 have also found to have a pathogenic role in emphysema .

In emphysema there is loss of both epithelial & endothelial cells as well as of mesenchymal cells leading to lack of extracellular matrix (ECM),the scaffold upon which epithelial cells would have been grown .Tobacco smoke contains abundant ROS i.e free radicals which deplete these anti-oxidants mechanisms , thereby inciting tissue damage .

Activated neutrophils add to the pool of ROS in the alveoli . Asecondary consequence of oxidative injury is inactivation of a native anti-protease resulting in functional alfa 1 antitrpsin deficiency even in normal individuals.

52 : Pathogenesis of emphysema .

Morphology of Emphysema :

The diagnosis & classification of E . largely depend on macroscopical appearance of thelung .In well-developed pan-acinar E. the lungs are pale voluminous hyperinflated it obscuresthe heart when

anterior chest wall is removed during autopsy .In centri -acinar E. the macroscopic features are less impressive , the lung look deeper pink than in pan-acinar E. and less voluminous , it tends to affectthe upper 2/3 of the lungs than the lower lung.

Histologically :

There is thinning & destruction of alveolar walls ,with advanceddisease the adjacent alveoli become confluent creating a large air-spaces .Terminal & respiratory bronchioles may be deformed because of loss of septa that help connecting them to the parenchyma, with loss of elastic tissue , there is a reduced radial traction of small airways resulting in their collapse duringexpiration, an important cause of chronic airflow obstruction in sever emphysema..In addition to alveolar loss a number of alveolar capillaries are diminished.

Microscopic view of emphysematous lung

tissue showing dilated alveolar spaces & destruction of

alveolar septa .

Clinical Features :

Dyspnoea is usually the first symptom , it begins insidiously but steadily progressive , with cough & wheezes .The patient with emphysema without concomitant chronicbronchitis usually presents with a barrel-chest & dyspnoea

and prolonged expiration .Dyspnoea & hyperventilation are prominent.The blood gases stay normal very late in disease due to prominent dyspnoea and hyperventilation there is adequate oxygenation of the blood caused by liberation oferythropoietin which stimulate the bone marrow to increase haematopoiesis leading to polycythemia and high level of haemoglobin .These patients are called Pink-puffer .

Photographic appearance

of pink puffer, an obese

patient with advanced

emphysema without

chronic bronchitis

having barrel-shaped

chest , dark red colored

skin due to

polycythemia .

On the other extreme are patients with emphysema who also have chronic bronchitis & a history of recurrent infections with purulent sputum .They usually have less prominent dyspnoea so they retain

carbon dioxide , they become hypoxic, often cyanotic

& for unknown reasons they tend to be obese .They are usually seeking medical help after theonset of congestive heart failure ( cor pulmonale ) . Such patients are called Blue bloater.

Photograph of emphysematous

patient with

chronic bronchitis (Blue bloater ),

a cyanotic patient with

bluish discoloration of skin &

mucous membranes .

Secondary pulmonary hypertension develops gradually arising from vascular spasm and loss of pulmonary

capillaries resulting from alveolar destruction.

Death in emphysema is related to either pulmonary failure with respiratory acidosis , hypoxia & coma or right heart failure i.e. cor

pulmonale .

Conditions related to Emphysema :

Compensatory emphysema :

A term used to describe a compensatory dilatation of alveoli in response to loss of lung substance as occurs inresidual lung parenchyma after surgical removal ofdiseased lung or lobe .

Obstructive over inflation :

Refers to a condition in which the lungs expand because air is trapped within it .A common cause is subtotal obstructiony atumor or foreign objects.

Obstructive over inflation can be life-threatening emergency if the affected portion extends to compress the remaining normal lung

Bullous emphysema :Refers to any form of emphysema that produce alarge sub pleural blebs or bullae i.e. air spaces large than 1cm. in diameter , when rupture lead to pneumothorax

Gross view of Bullous emphysema . Peripheral cystic

bulae may rupture causing pneum o thorax,i.e air within pleural cavities ,

Mediastinal ( interstitial ) emphysema :

Refers to entrance of air into the connective tissuestroma of the lung ,mediastinum & subcutaneous tissue .This may occur spontaneously due to increased in intra-alveolar pressure as withvomiting or cough that cause a tear with dissecting of air into the interstitium.May occur in children with whooping coughor fractured ribs.

When the interstitial air enters the subcutaneoustissues, the patient may literally blow up like a

balloon with marked swellingof the head and neck with crackling crepitations all over the chest .In most instances the air is resorbed spontaneouslywhen the site of entry is sealed.

Photograph of a patient

with interstitial

(mediastinal) emphysema.

Air is accumulating in

subcutaneous tissue of

mediastinum, the neck &

the face, following

fractured ribs.

Acute Respiratory distress syndrome

(ARDS):Also called shock lung ,or acute lung injury . It is a clinical

syndrome characterized by diffuse alveolar

capillary damage & clinically by sudden onset of severe

life- threatening respiratory insufficiency ,

cyanosis and severe arterial hypoxemia that is refractory to

oxygen therapy .

Chest X-ray shows diffuse alveolar infiltrate, due to diffuse

alveolar damage (DAD).

Pathogenesis :Clinical disorders are :

Direct lung injury :

Common causes :1 Pneumonias2 Aspiration of gastric content .

Uncommon causes :1 Pulmonary contusion.

2 Fat embolism.

3Near-drowning .

4- Inhalation injury .

5- Reperfusion after lung transplantation

Indirect lung injury :

1 Sepsis

2Severe trauma with shock.

3- Cardio-pulmonary bypass.

4- Acute pancreatitis .

5 Drug overdose .

6Transfusion of blood products .

7- Uremia

The alveolar capillary membrane is formed by two separate

barriers the microvascular endothelium and the alveolar

epithelium .

Pathogenesis :

In ARDS the integrity of this barrier is compromised either

by endothelial or epithelial injury or more commonly both.The acute consequence of the damage to this barrier include increased vascular permeability, alveolar

flooding i.e edema , loss of diffusion capacity & widespread

surfactant abnormalities caused by damage totype II pneumocytes .

As early as 30 minutes after acute injury there is increased synthesis of interleukin 8 by pulmonary macrophages . IL-8 is a potent neutrophil chemotactic& activating agent .

Neutrophils has an important role in pathogenesis of

ARDS .

The release of this mediator & other similar

compounds such as IL-1 & TNF leads to endothelial

activation & pulmonary micro-vascular sequestration Activated neutrophils release oxidants protease ,platelets activating factor and leukotriens that cause damage to alveolar epithelium .& maintain theinflammatory cascade .

Combined epithelial & endothelial injury lead to

increased vascular permeability & loss of surfactant

that render alveolar unit unable to expand .

The destructive force induced by neutrophils are

apposed by an array of endogenous antiprotease ,

anti-oxidants & anti- inflammatory cytokines e.g. IL-

10 that are unregulated by pro-inflammatory

cytokines

In the end the balance between the destructive

& the protective factors that determines the clinical

severity and the degree of tissue injury of ARDS.

Pathogen

es is of

ARDS

Morphology :

In the acute ARDS , the lungs are dark red ,firm airless and heavy .Microscopically:There is capillary congestion , necrosis of alveolar epithelialcells , interstitial and intraalveolar edema & hemorrhage andparticularly with sepsis i.e collection of neutrophils in capillaries .

The most characteristic finding is the presence of hayaline membrane particularly lining the distended alveolar ducts .Such membrane consists of fibrin- rich edema fluid admixed with reminants of necrotic epithelial cells .This is similar to that seen in respiratory distress

syndrome seen in the newborn in which

deficiency of pulmonary surfactant is the major

cause .

Microscopic view of ARDS ,showing hyaline membrane

deposition along alveolar septa (labeled with an arrow ) .

In the organizing stage there is marked proliferationof type II pneumocytes in an attempt to regeneratethe alveolar lining .Resolution is unusual , more commonly there is organization of the fibrin exudates with resulting intra-alveolar fibrosis .Marked thickening of alveolar septa ensues caused by proliferation of interstitial cells & deposition ofcollagen.

Clinical course :80% of patients develop the clinical symptoms of acute lung injury or ARDS within 72 hours of the initiating insult.The prognosis is gloomy and mortality rate reaches 100%.

The predicting factors in ARDS are-Age .- Underlying bacteremia or sepsis.- Development of underlying system failure as cardiac, renal or hepatic .If the patient could survive acute stage , then interstitial fibrosis occur and compromise respiratory function .If in patients who survive acute stage without the chronic sequelae , normal respiratory function returns within 6-12 months.

Pneumoconiosis

Is a non-neoplastic lung reaction to inhalation of mineral dusts.The term includes diseases caused by organic as well as inorganic particulates & some also include the chemical fumes and vapor-induced lung diseases.The most common & clinically significant lung diseases are those caused by the following mineraldusts :Coal dust SilicaAsbestos

Coal –mine workers are at high risk of

affected by anthracosis .

Pathogenesis of pneumoconiosis :The reaction of lung tissue to mineral dusts

depends on many variable :

(1)The amount of particles retained in the lung

&airways.

(2)The size the shape & the concentration of the

inhaled dust particles.

(3)Solubility & cytotoxicity of particles is influenced

by their size , the smaller the particles , the more

likely they appear in the pulmonary fluids & reach

the toxic levels rapidly.

Particles larger than 5-10 micrometer in diameter are unlikely

to reach distal airways , whereas particles smaller than 0.5

Mm tend to act like gases and move in & out of alveoli, often

without substantial deposition and injury .

Particles that are between 1-5 Mm in diameter are the most

dangerous , because they get lodged at the bifurcation of the

distal airways, and may reach the terminal small airways &

air sacs & settle in their linings .Most inhaled dusts are entrapped in mucus & rapidly removed from the lung by ciliary movement.Some dust particles become impacted at alveolar ducts bifurcations where macrophages accumulate andphagocytose the trapped particles .

Ultra structural view of Asbestos particles

( the Amphibole type ) straight stiff & brittle fibers .

The alveolar macrophages play a major role in the initiation

& perpetuation of lung injury & fibrosis .

The more reactive particles trigger the macrophages to

release a number of products that mediate an inflammatory

response & initiate fibroblastic proliferation & collagen

deposition .

Some of the inhaled particles may reach the lymphatics

either by direct drainage or the migrating macrophages &

thereby initiate an immune response to components of the

particles & or self proteins that are modified by the

particles.Tobacco smoking worsens the effects of all inhaled mineral dust, more severe with asbestos than with any other particle.

Coal- worker pneumoconiosis :

A condition affecting the coal- mine workers characterized by black lung usually with tuberculosis.Clinically it may be

1Asymptomatic anthracosis in which pigment accumulate without a perceptible cellular reaction .2simple coal worker pneumoconiosis (CWP) , in which accumulation of macrophages occur with littleto no pulmonary dysfunction .3Complicated CWP or progressive massive

fibrosis ( PMF) , in which fibrosis is extensive & lung function is compromised

Morphology :Pulmonary anthracosis is the most innocuous coal-induced pulmonary lesion in coal minors & is also seen in urban dwellers& tobacco smokers .Inhaled carbon particles are engulfed by alveolar & interstitial macrophages & then accumulate in the connective tissue along the lymphatics, including thepleural lymphatics &in lymph nodes .

Simple coal-worker pneumoconiosis :Is characterized b coal macules & somewhat larger

coal nodules.The coal macule consists of dust-laden macrophages inaddition the nodule contains small amount of a network of collagen fibers.Although these lesions are scattered throughout the lung, the upper lobes & upper zones of lower lobes are more heavily involved in due course,Centrilobular emphysema can coexist.

Gross appearance of the

lung in simple coal worker

pneumoconiosis. Black

carbon particles seen in

upper lobes.

Simple coal workers

pneumoconiosis i.e.

Anthracosis,

microscopic view

showing carbon

particles deposited

in peri bronchial

tissue within

macrophages &

extra cellularly.

Complicated CWP ,also called progressive

massive fibrosis (PMF):Occurs on a background of simple CWP by coalescence of coal nodules and generallyrequiresmany years to develop. It is characterized by intensely blackened scars larger than 2cm. sometimes up to10cm. in greater diameter. They are usually multiple. Microscopically: the lesion consists of dense collagenand pigment.

Gross view of massive

pulmonary fibrosis

dense fibrosis of lung

tissue, overlapping

dense carbon particles

deposition.

Microscopic view of complicated coal worker pneumoconiosis showing

black carbon particles deposits with fibrosis & emphysematous

Silicosis :Is currently the most prevalent chronic occupational disease in theworld. It is caused by inhalation of crystalline silica. Quartz is the most commonly implicated in silicosis.Morphology : Silicotic nodules are characterized grossly in their early stages by tiny palpable , discrete , pale to blackened nodules inthe upper zones of the lungs . Silicotic patients have increasedsusceptibility to tuberculosis . Combined silicosis & rheumatoid arithritis with pleural effusion is referred to as Caplan’s syndrome .Microscopically:The silicotic nodule demonstrate a concentrically arranged hyalinized collagen fibers surrounding the amorphous center .

Silica crystal .

Microscopic view of silicotic nodule consisting of dense

collagen deposition & fibrosis.

Asbestosis

Asbestos and asbestos-related diseases

Occupational exposure to asbestos is

linked to:

1Paranchymal interstitial fibrosis (

asbestosis ).

2Localised fibrous plaques .

3- Pleural effusions.

4 Bronchogenic carcinoma .

5Malignant pleural & peritoneal

mesothelioma .

Pathogenesis :

Concentration, size, shape & solubility of

the different forms of asbestos dictate

whether disease will occur. There are two

distinct forms of asbestos:

Serpentine chrysotile in which the fiber

is curly & flexible.

Amphibole in which the fiber is straight

stiff & brittle.

Ultra structural view of Asbestos particles (the Amphibole

type) straight stiff & brittle fibers.

Microscopic view of Asbestosis showing Asbestos body

within macrophages.

Asbestosis like other pneumoconiosis, causes

fibrosis by inter acting with lung

macrophages. In addition to cellular & fibrotic

lung reaction, asbestos also functions as both

a tumor initiator and a promoter. For example ,

the adsorption of carcinogens in tobacco

smoke on to asbestos fibers may well be

important to the remarkable synergy between

tobacco smoke and the development of

bronchogenic carcinoma in asbestos workers.

Morphology

Asbestos is marked by a diffuse pulmonary

interstitial fibrosis , with the presence of asbestos

bodies which are seen as golden brown fusiform or beaded rods with a translucent center, they consist ofasbestos fibers coated with an iron –containingproteinaceous material. Similarly the visceral pleura undergoes fibrous thickening and sometimes binds thelungs to the chest wall.

Microscopic view of pulmonary fibrosis with asbestos particles

within alveolar spaces labeled by arrow.

Pleural plaques:

• Are the most common manifestation of asbestos exposure and are awell circumscribed plaques of dense collagen often containing calciumthey develop on the anterior & posterior aspects of the parietal pleura &overlap the diaphragm. They do not contain asbestos bodies , they onlyrarely occur in persons who have no history of asbestos exposure.Uncommonly asbestos exposure induces pleural effusions which areusually serous but may be bloody. Both bronchogenic carcinoma as wellas both pleural & peritoneal mesotheliomas has an association withasbestos exposure.

Gross view of pleural plaques seen on diaphragms in

patient with chronic asbestosis.

Sarcoidosis :

A multisystem disease of unknown etiology characterized

by non-caseating granulomas in many tissues & organs.

The diagnosis of sarcoidosis is always by exclusion from

other conditions producing non-caseating granulomas

like Berylliosis, mycobacterial & fungal infections.

Bilateral hilar lymphadenopathy or lung involvement or

both, visible on chest x-ray is the major presenting

manifestation in most cases. Eye & skin involvement

each occurs in 25% of cases & may be the presenting

features of disease. The liver ,spleen ,bone marrow &

skeletal muscle, salivary glands ,CNS & other sites may

be involved.

Epidimiology:

Sarcoidosis occurs throughout the world affecting both sexes & all ages races. They tend to affectadults younger than 40 years of age. A high incidence among US African American in whom thefrequency of involvement is 10 times greater than US-American Caucasians. Sarcoidosis have higherprevalence among nonsmokers.

Etiology & pathogenesis :Although the etiology of sarcoidosis remain unknown , some of the evidence suggest that it is a disease ofdisordered immune predisposed individuals exposed to

regulation in geneticallycertain

environmental agents. Genetic influences in individualswith sarcoidosis are suggested by familial & racialclustering of cases & association with certain humanleukocytes antigens like Class 1 HLA1,HLB2 genotype.

Chest X-ray of

patient with

sarcoidosis

showing multiple

lung opacities.

Morphology : Non-caseating granulomas is the characteristichistological feature of sarcoidosis irrespective of organinvolved. This is discrete, compact collection ofepithelioid cells rimmed by an outer zone of CD+ Tcells. A thin layer of laminated fibroblasts is presentperipheral to granuloma over time these proliferate &lay down collagen. Two other microscopic features arecommonly seen in granuloma are:Schaumann bodies are laminated concressionscomposed of calcium & protein.Asteroid bodies: stellate inclusions enclosed withingiant cells .

Microscopic view of sarcoidosis . Non-caseating granulomas .

Microscopic view of non-caseating granuloma with giant cell in

sarcoidosis

The lungs are involved in 90% of patients . Thegranulomas frequently involve the interstitium ratherthan the airspaces with some tendency to localize inthe connective tissue around bronchioles & pulmonaryvenules & in the pleura i.e lymphangitic distribution.Intra thoracic & paratracheal lymph nodes areenlarged in 75% to 90% of patients.The lymph nodes are painless , firm rubbery , unlike TB

lymph nodes in sarcoidosis are non-adherent & non

caseating. Hypercalcemia & hypercalcuria , are

common features . This is not due to bone destruction ,

but due to increased calcium absorption secondary to

production of active vitamine D by mononuclear

phagocytes in the granuloma .

Microscopic

view of

sarcoidosis

showing

concentrically

calcified

Schaumann

body.

High power view of

Schaumann body, a

concentrically

calcified body seen

within giant cell in

sarcoidosis.

Clinical course:

In many individuals the disease is discoveredon routine chest film as bilateral hilarlymphadenopathy or incidently duringautopsy. Hepatomegally & splenomegally

may be present. In 1/3 of symptomatic casesthere is partial appearance of respiratorysymptoms (shortness of breath, cough &vague substernal discomfort). Constitutionalsymptoms including fever, fatique, nightsweats & anorexia. Lung & lymph node biopsyshow non-caseating granulomas.

Photograph showing eye & skin involvement by sarcoidosis .

Atelectasis ( Collapse):Is loss of lung volume caused

resultsby inadequate in shunting ofexpansion of airspaces. It

inadequate oxygenated blood from pulmonaryarteries into veins thus giving rise to a ventilation –

perfusion imbalance & hypoxia.

Classified into three forms :I-Resorption atelectasis :

Occurs when obstruction prevents air from reaching distal

airways . The air already present becomes absorbed &

alveolar collapse follows. Depending on the level of

airway obstruction an entire lung , a complete lobe or

one or more segments may be involved. The most

common cause of bronchial obstruction is mucus or

mucopurulent plug, accumulate post operatively , may

complicate bronchial asthma, bronchiectasis , chronic

bronchitis or aspiration of foreign bodies particularly in

children.

II. Compression atelectasis :

Sometimes called passive or relaxation atelectasis is usually

associated with accumulation of fluid , blood or air within the

pleural cavity, which mechanically collapse the adjacent

lung. This frequently occur with pleural effusion caused most

commonly by congestive heart failure . Leakage of air in

pleural cavity called pneumothorax also causes compression

atelectasis.

III. Contraction atelectasis :

Contraction or cicatrisation atelectasis occurs when either

local or generalized fibrotic changes in the lung or pleura.Atelectasis is potentially reversible & should be treatedpromptly to prevent hypoxia & super imposed infection of thecollapsed lung.

Diagram showing types of

lung atelactasis (collapse)

resorption, compression &

contraction types.

Pulmonary Hypertension

Normal pulmonary blood pressure is 1/8 of

systemic blood pressure i.e. 15/10mmHg.

Pulmonary hypertension is considered

when the mean pulmonary pressure

exceeds ¼ the systemic blood pressure.

(30/ 20mmHg). It is most frequently

secondary to structural cardiopulmonary

conditions that increase pulmonary blood

flow or pressure or both.

Causes of pulmonary hypertension :

1Chronic obstructive or interstitial lungdisease: cause hypoxia as well as destruction of lungparenchyma& hence have fewer alveolar capillariesthis increases pulmonary arterial resistance andincrease blood pressure.2Congenital or acquired heart diseases asmitral valve stenosis because of increase in left atrialpressure leading to increased pulmonary venouspressure & consequently increased pulmonary arterialpressure.

3- Recurrent thrombo-emboli: due to reduction inthe functional cross sectional area of pulmonaryvascular bed brought about by obstructing embolilead to increase in pulmonary vascular resistance .

4- Auto-immune disorders: as systemic sclerosisinvolving pulmonary vasculature leading to

inflammation, intimal fibrosis medial hypertrophy &pulmonary hypertension.

5- Primary or idiopathic pulmonary hypertension: when all the above causes are absent . 6% of cases are familial form due to autosomal dominant mode of inheritance.

Pathogenesis :

The primary familial pulmonary hypertension is caused by

mutations in Bone morphogenic protein receptor type 2(BMPR2) signaling pathway. In secondary pulmonaryhypertension: endothelial cell dysfunction is produced bythe process that initiate the disorder, & mechanical injuryassociated with left to right shunts or the biochemicalinjury produced by fibrin in thromboembolism. Decreasedelaboration of prostacycline and nitric oxide andincreased release of endothelin all promote pulmonaryvasoconstriction. Pulmonary hypertension as beenreported following ingestion of certain plants as Crotalariaspectabilisin tropics & used medicinally as bush tea , aswell as the apatite depressant agent aminorex ,adultrated olive oil and anti obesity drugs.

Morphology :

Vascular alterations in all forms of pulmonary hypertension

(primary or secondary) involve the entire arterial tree.

1 I n main elastic arteries atheroma seen.

2In medeium-sized muscular arteries proliferation of myo intimal

cells & smooth muscle cells causing thickening of the intima and

media with narrowing of the lumina.

3In smaller arteries & arterioles thickening , medial

hypertrophy & reduplication of the internal & external

elastic membranes may cause complete obliteration of the lumen.

Clinically :

Primary pulmonary hypertension is almost

always encountered in young persons more

common among women, marked by fatigue,

syncope on exercise, dyspnoea on

exertion & sometimes chest pain, may develop

severe respiratory insufficiency & cynosis.

Death result from right sided heart failure, cor

pulmonale develop within 3- 5 years after

diagnosis.

Good pasture syndrome :

A diffuse hemorrhagicinterstitial alveolar disease, an uncommon condition characterized by a proliferativeusually progressive glomerulonephritis & hemorrhagic interstitial pneumonitis. Both renal & pulmonary lesionscaused by an antibody targeted against collagen type IV

i.e. (basement membrane). These antibodies are seen in 90% of patients.

Morphology:

In classic diffuse alveolar hemorrhage , the lungs are heavy with areas of red brown consolidations.Microscopically: Necrosis of alveolar walls with thickening

of the septa & hypertrophy of septal lining cells. The

presence of hemosiderine either within macrophages or

extra cellularly is seen few days after presentation. IgG,

Igm & IgA seen in renal biopsy & in alveolar septa.

Plasmapheresis & immunosuppressive therapy improved

the prognosis of the disease.

Plasma exchange remove the offending antibodies &

immunosuppressive therapy inhibit antibody production.

Gross appearance of

lungs in Good Pasture

syndrome. Red lungs

due to pulmonary

hemorrhage.

Microscopic view of lung in Good Pasture syndrome showing

recent (left) & old (right) intra alveolar hemorrhage.