Chronic Obstructive Pulmonary
Diseases
Chronic Bronchitis
Emphysema
Bronchiectasis
Bronchial Asthma
Small Air way disease Bronchiolitis
Pathogenesis
• Prolonged exposure to cigarette smoke and/or other air
pollutants.
• Airway obstruction
– at times may result in a check-valve mechanism
– leading to overdistension and rupture of alveolar septa,
especially if the latter are inflamed and exposed to high
positive pressure (i.e. barotrauma).
• With loss of alveolar surface in emphysema, there is a
decrease in surface tension, resulting in expiratory
airway collapse.
• Additional investigative work continues in an effort to
link disease states to pathogenesis
Etiology
• By far the most common etiological cause of
COPD remains smoking. Even after the client
quits smoking, the disease process continues to
worsen.
• Air pollution
• and occupation also play an important role in
COPD.
• Smog and second-hand smoke contribute to
worsening of the disease.
Cont.
• Occupational exposure to irritating fumes and
dusts may aggravate COPD.
• Silicosis and other pneumonoconioses may bring
about lung fibrosis and focal emphysema.
• Exposure to certain vegetable dusts, such as cotton
fiber, molds and fungi in grain dust, may increase
airway resistance and sometimes produce
permanent respiratory impairment.
Cont.
• Exposures to irritating gases, produce pulmonary
edema, bronchiolitis and at times permanent
parenchymal damage.
– Chlorine
– Oxides of nitrogen and sulfur,
– Repeated bronchopulmonary infections can also
intensify the existing pathological changes, playing a
role in destruction of lung parenchyma and the
progression of COPD.
Chronic Bronchitis
•
Definition: Chronic bronchitis is a clinical
syndrome defined by chronic sputum production
–
–
–
–
•
Persistent cough
with sputum production
for at least 3 months
in at least 2 consecutive years
Anatomic site
–
Bronchus
Morphology
• Hyperemia and edema of mm of lungs
• Mucinous secretions or casts filling in the air ways
• Increase in the size and numbers of mucous
secreting glands
• Bronchial or bronciolar mucous plugging, fibrosis,
inflammation and fibrosis
• Squamous metaplaisa or dysplasia of bronchial
epithelium
Chronic Bronchitis Pathophysiology
Chronic
inflammation
Cilia
Damaged
Hypertrophy
&
hyperplasia of bronchial
glands that secrete mucus
Increase
number of goblet
cells
Cilia
are destroyed
Chronic Bronchitis Pathophysiology
• Narrowing of airway
– Starting w/ bronchi 
smaller airways
• airflow resistance
• work of breathing
• Hypoventilation & CO2
retention  hypoxemia &
hypercapnea
Chronic Bronchitis Pathophysiology
• Bronchospasm often occurs
• End result
–
–
–
–
–
Hypoxemia
Hypercapnea
Polycythemia (increase RBCs)
Cyanosis
Cor pulmonale (enlargement of right side of heart
Cartilage damage in long standing
cases
• Degenerative changes, atrophy and loss of
bronchial cartilage were common features of
most chronic bronchitic specimens
• This usually being related to intrinsic changes
in the chondrocyte phenotype, including
proliferative and matrix-degrading properties.
• Mast cells and macrophages were often
observed in close association with the bronchial
cartilage,
– suggesting that inflammatory cells may also
contribute to the mechanisms of bronchial cartilage
degradation and loss
Inflammatory Cells
• Studies show that smokers with symptoms of
chronic bronchitis have an increased number
of inflammatory cells in their bronchial glands
when compared with asymptomatic smokers.
• This inflammatory process consists
predominantly of neutrophils and
macrophages, and of an increased proportion
of CD8+ T-lymphocytes
• Mast cells
Mast cells
Lymphocytes
Neutrophils
Macrophages
Macrophages, Mast cells, Lymphocytes and Neutrophils
Neutrophils
Lymphocytes
Macrophages
Mast cells
This inflammatory
process consists
predominantly of
neutrophils and
macrophages, and
of an increased
proportion of
CD8+ Tlymphocytes and
Mast Cells
Pathogenesis
• Chronic irritation of airways
– Smoking
– Dust
– Air pollutants etc
• The major risk factor for the development of
chronic bronchitis is cigarette smoking
• Infective agents Secondary factor
• These irritants cause
–
–
–
–
Hypersecretions of mucous
Subsequent hypertrophy of mucous glands
Metaplasia
inflammation
Emphysema
• Pulmonary emphysema is
described in clinical,
radiological and
physiologic terms, but the
condition is best defined
morphologically
• Definition:Abnormal
enlargement of airspaces
distal to the terminal
bronchioles with
destruction of their wall
• It is characterized by
destruction and
enlargement of alveoli
Cont.
• Although the normal lung has about
35,000 terminal bronchioles and their
total internal cross-sectional area is at
least 40 times as great as that of the
lobar bronchi but the bronchioles are
more delicate and vulnerable.
Cont
• Bronchioles may be obstructed partially
or completely, temporarily or
permanently, by thickening of their
walls, by collapse due to loss of
elasticity of the surrounding
parenchyma, or by influx of exudates.
Cont
• In advanced emphysema, the lungs are
large, pale, and relatively bloodless.
• They do not readily collapse.
• They many contain many superficial
blebs or bullae, which occasionally are
huge.
• The right ventricle of the heart is often
enlarged (cor pulmonale), reflecting
pulmonary arterial hypertension.
Emphysema: Pathophysiology
• Structural changes
– Hyperinflation of
alveoli
– Destruction of alveolar
& alveolar-capillary
walls
– Small airways narrow
– Lung elasticity
decreases
Emphysema
• Loss of Lung Surface Area for
Gas Exchange and Oxygen
Transport
• Loss of Lung Surface area is
due to death of Lung
Endothelial Cells
• Polycyclic aromatic
hydrocarbons (PAHs) in
Cigarette Smoke and in
Environmental Pollution may
cause endothelial cell death
Emphysema: Pathophysiology
• Mechanisms of
structural change
• Obstruction of small
bronchioles
• Proteolytic enzymes
destroy alveolar tissue
• Elastin & collagen are
destroyed
– Support structure is
destroyed
– “paper bag” lungs
Emphysema: Pathophysiology
• The end result:
• Alveoli lose elastic recoil,
then distend, & eventually
blow out.
• Small airways collapse or
narrow
• Air trapping
• Hyperinflation
• Decreased surface area for
ventilation
Emphysema:
Clinical Manifestations
• Early stages
–
–
–
–
Dyspnea
Non productive cough
Diaphragm flattens
A-P diameter increases
• “Barrel chest”
– Hypoxemia may occur
• Increased respiratory rate
• Respiratory alkalosis
– Prolonged expiratory phase
• Tripod position
Emphysema:
Clinical Manifestations
• Later stages
–
–
–
–
Hypercapnea
Purse-lip breathing
Muscle retraction
Use of accessory muscles to
breathe
– Underweight
• No appetite & increase
breathing workload
• Loss of subcutaneous fat
– Lung sounds diminished
Clinical Manifestations
• Pulmonary function
•  residual volume,  lung
capacity, DECREASED
FEV1, vital capacity
maybe normal
• Arterial blood gases
– Normal in moderate disease
– May develop respiratory
alkalosis
– Later: hypercapnia and
respiratory acidosis
• Chest x-ray
– Flattened diaphragm
– hyperinflation
Classification
• Anatomical Distribution
–
–
–
–
Cetriacinar
Panacinar
Paraseptal
Irregular
Pathogenesis
• Protease anti Protease Theory
– Hereditary deficiency of the major protease inhibitors
– Laurell and Eriksson –1963 – deficiency of α1-antitrypsin
and emphysema
• Pollutants in environment
– smoking of cigarettes
– exhalations from cars, dust from grain
• Recruitment of neutrophils
• stimulation of macrophages and epithelial cells to produce TNFα, IL-8 and LTB4
• Elastase release from leukocytes and tissue macrophages
• Inactivation of α1-antitrypsin by oxidants in tobacco smoke or
free radicals released from the neutrophils
Diseases in which misfolding of a given
protein results in improper trafficking
Diseases in which misfolding of a
given protein results in improper
trafficking
polymers of alpha1 antitrypsin molecules will form.
These will be retained in the liver (where alpha1
antitrypsin is produced) and will not reach the lungs
Copyright ©2005, The Regents
of the University of California
hyper aeration
increased
lung
lucency
decreased
vessel size
Emphysema – Total
Lung Capacity (TLC) &
Residual Volume (RV) are elevated. P = 2t/r.
Flattening of the
Diaphragm
Decreased Peripheral
Vascular Markings
Increased Lung
Height
Chest X-Ray Changes in Emphysema:
• The two primary findings are:
1. Increased Lung Volumes, i.e., hyperaeration or
overinflation.
2. Lung Destruction (bullae or decreased vascularity which
gives increased lung lucency and decreased vessel size ).
• In end-stage disease, emphysema and chronic obstructive
pulmonary disease can result in pulmonary arterial
hypertension and eventually cor pulmonale (cp) - which
causes an increase in the pulmonary arterial size, as well as
right ventricular enlargement and cardiomegaly.
Normal acinus
Morphology
Panlobular Emphysema
Centrilobular Emphysema
Paraseptal
Peripheral alveolar
damage
© Univ of AL at Birmingham, Dept. of Path.
Bullous Emphysema
Other types of Emphysema
1 Bullous Emphysema (also known as
Bullous Lung Disease):
Bullous emphysema is so named when there
are multiple large bullae associated with a
compromise in pulmonary function. It is
usually associated with concomitant
emphysema, although occasionally, it can
be familial
Bullous Emphysema
•
Subpleural Type: These subpleural bullae contain only gas
with no alveolar remnants or blood vessels. They are often
located in the apex of the upper lung zone, and along the
costophrenic rim of the middle lobe and lingua, but may be
seen in the vicinity of parenchymal scars.
• Superficial Type: These bullae are found along the anterior
edge of the upper and/or middle lung zones, or lingula, and
over the diaphragms. They contains blood vessels and
strands of partially-destroyed lung.
• Deep Type: These bullae are found within the lung substance
and contain strands of partially-destroyed lung tissue and
blood vessels.
2.Giant Bullous Emphysema: ("Vanishing Lung Syndrome"
or "Primary Bullous Disease of the Lungs")
• It
is usually associated with young males
who show large progressive upper lung
zone bullae that are often asymmetric.
• The giant bullous lesions occupy greater
than or equal to one-third of the hemithorax.
Cont.
3.Focal Dust Emphysema ( This is focal emphysema
surrounding silicotic nodules.
• 4.Congenital Lobar Emphysema (CLE)
5.Interstitial Emphysema
Bronchiectasis
• Bronchiectasis is a chronic lung disease that is
characterized by permanent dilatation of
the bronchi and fibrosis of the lung.
• It is defined as the pathological, irreversible
dilation of bronchi , due to destruction of the
bronchilal walls and their supporting tissues
• It is highly associated with chronic bacterial
infection
• Often looked at, as the final common pathway
of many injurious processes
NCI
Clubbing is not a feature of COPD alone.
If clubbing is found, search for lung cancer.
Cont.
• Bronchiectasis , although uncommon,bears
the potential to cause severe illness ,
including repeated respiratory infections ,
disabling cough, purulent sputum, shortness
of breath,
• chest pain and occasionally hemoptysis, with
significant impact on the health and the quality
of life of the affected person
Types of Bronchiectasis
• Bronchiectasis
means
irreversible
dilation and distortion of the bronchi and
bronchioles.
• Pathologically, bronchiectasis can be
divided into four types
Cylindrical Bronchiectasis
• The first type, cylindrical bronchiectasis, is
characterized by uniform dilatation of bronchi,
that extends into the lung periphery, without
tapering.
• Tubular bronchiectasis is simply the absence of
normal bronchial tapering and is usually a
manifestation of severe chronic bronchitis rather
than of true bronchial wall destruction
Bronciectasis
Cylindrical Forma
Varicose Bronchiectasis
• The second type is called varicose
bronchiectasis and is characterized by
irregular and beaded outline of bronchi,
with alternating areas of constriction and
dilatation.
Saccular Bronchiectasis.
• The third type is called cystic or saccular
bronchiectasis and is the most severe form of
the disease.
• The bronchi dilate, forming large cysts, which
are usually filled with air and fluid.
• Saccular bronchiectasis is the classic
advanced form characterized by irregular
dilatations and narrowing.
• The term cystic is used when the dilatations
are especially large and numerous
Bronchiectasis
Saccular Form
Follicular Bronchiectasis
• The fourth type of bronchiectasis is called
follicular and is characterized by extensive
lymphoid nodules within the bronchial
walls.
• It usually occurs following childhood
infections
Cont.
• Repeated or prolonged episodes of
pneumonitis,
• Inhaled foreign objects or
• Neoplasms have been known to cause
bronchiectasis.
• When the bronchiectatic process involves
most or all of the bronchial tree, whether in
one or both lungs, it is believed to be genetic
or developmental in origin
ASTHMA
• Definition
• Asthma is a chronic inflammatory
disorder of airways.
• Many cells and mediators are involved in
this process – eosinophils, mast cells and
T-lymphocytes.
Asthma
•
•
•
•
•
Reversible inflammation & obstruction
Intermittent attacks
Sudden onset
Varies from person to person
Severity can vary from shortness of breath
to death
Bronchial Hypersensitivity
• Chronic inflammation is connected with bronchial
hyperreactivity
–
–
–
–
–
and leads to episodes of wheezing,
coughing,
tightness in the chest,
breathlessness,
shortage of breath specially at night and in the morning.
• This episodes are usually connected with variable
obstruction which is reversible spontaneously or by
treatment.
Types
• A) Allergic asthma
– asthma induced by immunological mechanisms.
– IgE induced asthma
– IgE antibodies triggers early and late-phase of
response,
– T- lymphocytes late and opožděné responses.
• B) Non-allergic asthma
– asthma induced by non-immunological triggers
Intermittent and persistent
Response of Inflammation
• Inflammation causes obstruction of
airways by:
– Acute bronchoconstriction
– Swelling of bronchial wall
– Chronic production of mucous
– Remodeling of airways walls
Risk factors:
• Individual predisposition
–
–
–
–
–
genetic variability – 5. a 11. chromosome
atopy,
bronchial hyperreactivity,
male or female,
nation
• Environment
–
–
–
–
–
–
–
–
exposition to allergens
professional chemicals which lead to sensitivity,
viral and bacterial infection,
food,
smoking,
social and economic society,
number of family members,
psychosomatic influence
Asthma: Pathophysiology
• Swelling of mucus membranes (edema)
• Spasm of smooth muscle in bronchioles
– Increased airway resistance
• Increased mucus gland secretion
Asthma: Pathophysiology
• Early phase response: 30 – 60 minutes
– Allergen or irritant activates mast cells
– Inflammatory mediators are released
• histamine, bradykinin, leukotrienes, prostaglandins, platelet-activatingfactor, chemotactic factors, cytokines
– Intense inflammation occurs
• Bronchial smooth muscle constricts
• Increased vasodilation and permeability
• Epithelial damage
– Bronchospasm
• Increased mucus secretion
• Edema
Late phase response: 5 – 6 hours
– Characterized by inflammation
– Eosinophils and neutrophils infiltrate
– Mediators are released
mast cells release
histamine and additional mediators
– Self-perpetuating cycle
– Lymphocytes and monocytes invade as well
– Future attacks may be worse because of
increased airway reactivity that results from late
phase response
• Individual becomes hyperresponsive to specific allergens
and non-specific irritants such as cold air and dust
• Specific triggers can be difficult to identify and less
stimulation is required to produce a reaction
Cells involved in chronic allergic
inflammation
•
•
•
•
•
1. Eosinophils
2. Mast cells
3. T-lymphocytes
4. Neutrophils
5. Basophils
T-lymphocytes
NEUTROPHIL
•Basophil
s
Macrophage
•Eosinophils
Mast cell
Pathogenesis
• Acute inflammation
• Remodeling of airways
• Chronic inflammation
• Symptoms
– of bronchoconstriction
• Exacerbation
– nonspecific hyperreactivity
• Ongoing
– obstruction of airway
Remodeling
• destruction of brush epithelium in
airways
• swelling of the bronchial wall
• stimulation of proliferation of fibroblasts
• deposition of collagen in lamina
reticularis of basal membrane
• hypertrophy of smooth muscles
• hyperplasia of goblet cells
The process of remodeling is involved
by:
•
•
•
•
•
•
•
•
•
•
•
•
Th2 lymphocytes (CD25+, production of IL-4,13,5,6,10)
antigen presenting cells
mast cells (tryptase-converting angiotensin I to angiotensin II,
hypertrophy of smooth muscles, histamin – fibrogenetic effect)
eosinophils (long-living in epithelium and submucoses, create
lipids –PAF, LTC4,LTD4, LTB4, peptides, cytokines, TGF-α,
TGF-β, IL-1,3, GM-CSF, ECP)
alveolar macrophages (production of TNF-α, IL-6)
epithelial cells (desquamation of epithelium, lost of integrity,
TGF-β, IGF-1, KGF- β, alteration of differentiation and
proliferation of epithelial cells, apoptosis)
endothelial cells
Cont.
•
•
•
•
•
•
•
•
myocytes (proliferation of myocytes - after stimulation with IL11, which is produced by mezenchymal cells after stimulation
with allergen, PGDF, EGF, the effect of gelatinase A (MMP-2)
and B (MMP-9), production of IL-6,8, eotaxin, PGE2, RANTES,
MCP-1,2,3, expression of ICAM-1, VCAM-1, production of NO,
GM-CSF, IL-5)
fibroblasts (activation of fibroblasts, creation of
myofibroblasts, release of GM-CSF and TGF-β, increasing
proinflammatory
• activity of eosinophils)
Subepithelial structures:
• thickness of basal membrane
• increasing deposition of extracellular matrix under
epithelium
• deposition of collagen I., III., IV., V. and VII. in
reticular membrane
• increasing deposition of proteoglycans (lumican,
biblycan,
• decorin, fibromodulin, hyaluron, versica)
• tenascin (corresponds with activity of chronic
inflammation)
• fibronectin
Increasing number of
mucous glands
Increasing number of
smooth muscles fibres
Sever bronchospasms
during exacerbation
Increase of mucous secretion
during
Release of fibrogenetic
factors
Ongoing of inflammatory cells
Elastolysis
Inflammation
Decrease of
elasticity of the
wall
Deposition of collagen
in basal and Epithelial
membranes
Cytokines involved in pathogenesis of
asthma
• IL-4
• - cross-linking of immunoglobulines in B lymphocytes – production
of IgE and
• IgG4
• - increases of expression of VCAM-1 and mucous secretion
• - inhibits of activation of Th1 and production of IFNγ
• IL-13
• - induces production of IgE a IgG4
• - activates mast cells
• - increases bronchial hyperreactivity and contractility of smooth
muscles, affects
• the differentiation of cilia
• - induces the production of eotaxin, VCAM-1
• - suppress production of pro-inflammatory cytokines
Cont.
• IL-5
• - produced by mast cells and Th2 lymphocytes, epithelial cells and
eosinophils
• - affects the proliferation and the differentiation of B lymphocytes
• - induces expression of IL-2R
• - proliferating and differentiating factor for eosinophils
• IL-12
• - produced by macrophages, dendritic cells and monocytes
• - decreases production of Th2 cytokines and then production of IgE and
IgG1
• - decreases number of eosinophils in peripheral blood and in sputum
Cont.
• IL-10
• - large immunosupressive and anti-inflammatory
effect
• - decreases expression of iNOS, COX2
• decreases release of IL-2, expression of MHC class
II., CD80, CD86 and
• CD32 on the surface of APC and then presentation of
allergen, RANTES, IL-5
• - correlation with asthma severity
Cont.
• - IFNγ
• - low levels in atopic people
• - stimulatory effects on Th1 cells, inhibitory effects on Th2 cells
• - the nebulissation of IFNγ decreases the number of eosinophils
in BAL but this effect is not significant
• TGF-β
• - remodeling
• - induction of expression of Fas receptor on the surface of
epithelial cells,
• activation of apoptosis, phagocytosis by macrophages, exudation
of plasma,fibrosis
Etiological Classification of
asthma:
• A. Atopic (allergic) asthma
• - in combination with allergic rhinitis, atopic dermatitis, genetic
predisposition
• - confirmation of spec. IgE antibodies, prick tests, inhalation
challenge
• B. Endogenous asthma
• - without specific known influence, obviously in women after
exposition to cold
• weather, refract to the standard therapy
• C. Exercise induced asthma
• - physical exercising, provocation by inhalation of chemicals,
cold or hot
• weather
Cont.
• D. Aspirin induced asthma
• - typical triads-nasal polyps, urticaria and asthma induced by
application of
• aspirin
• - other drugs
• E. Allergic bronchopulmonary aspergillosis
• - aspergillus acts as an allergen challenge in atopic people and
induces
• aspergillus asthma or alergic bronchopulmonary aspergillosis
• - in the chest radiography are intermitent infiltrates in lungs, the
viscosity of
• mucous is increased and mucous plugs, bronchiectasia
Cont.
•
•
•
•
•
•
•
•
F. Gastroesophageal reflux
- bronchospasm induced by reflex
G. Sinobronchial syndrome
- combination of sinusitis with nasal polyps and with
asthma
H. Professional asthma
- induced by inhalation and exposition to industry
chemicals
CH. Asthmatic equivalent
- dry cough, irritating, without breathlessness
Classification of grading of asthma
• Grade 1. Intermitent asthma
• - rare symptoms < than 1x per week, short episodes of
worsening
• - night symptoms 2x monthly
• - no symptoms between attacks
• - PEF or FEV1 > 80%, variability < 20%
• Grade 2. Mild persistent asthma
• - symptoms <1x per day >1x per week
• - night symptoms > 2x per month
• - exacerbation can affect daily activity or sleeping
• - PEF or FEV1 > 80%, variability 20-30%
Cont.
•
•
•
•
•
•
•
•
•
•
•
•
Grade 3. Moderate persistent asthma
- Everyday symptoms
- Exacerbation affects daily activity and sleeping
- Night symptoms > 1x per week
- Everyday use of releasing drugs
- PEF or FEV1 between 60- 80%, variability > 30%
Grade 4. Severe persistent asthma
- Continuous symptoms
- Frequent exacerbation
- Physical activity is decreased
- Frequent night symptoms
- PEF or FEV1 < 60%, variability > 30%
Asthma: Early Clinical Manifestations
•
•
•
•
•
•
•
•
Expiratory & inspiratory wheezing
Dry or moist non-productive cough
Chest tightness
Dyspnea
Anxious &Agitated
Prolonged expiratory phase
Increased respiratory & heart rate
Decreased PEFR
Asthma: Early Clinical Manifestations
• Wheezing
• Chest tightness
• Dyspnea
• Cough
• Prolonged expiratory phase [1:3 or 1:4]
Asthma: Severe Clinical Manifestations
•
•
•
•
•
•
•
•
Hypoxia
Confusion
Increased heart rate & blood pressure
Respiratory rate up to 40/minute & pursed lip
breathing
Use of accessory muscles
Diaphoresis & pallor
Cyanotic nail beds
Flaring nostrils