MEDICINE (Dr.

PEDROZA)

COPD

14 FEBRUARY 2018

COPD INFLAMMATION AND ECM PROTEOLYSIS

ü defined as a disease state characterized by airflow limitation that is
not fully reversible Upon exposure to oxidants from cigarette smoke, macrophages and
ü includes: epithelial cells become activated, producing proteinases and
Ö emphysema, an anatomcally defined condition chemokines that attract other inflammatory and immune cells.
characterized by destruction and enlargement of the
lung alveoli;
Ö chronic bronchitis, a clinically defined condition with
chronic cough and phlegm;
Ö small airways disease, a condition in which small shifting the balance toward CD8+ T cells are also recruited in
bronchioles are narrowed. acetylated or loose response to cigarette smoke
ü COPD is present only if chronic airflow obstruction occurs; chronic chromatin, exposing nuclear and release interferon-inducible
bronchitis without chronic airflow obstruction is not included within factor-κB sites, and resulting pro- tein-10 (IP-10, CXCL-7),
COPD. in transcription of matrix which in turn leads to
PATHOGENESIS metalloproteinases, macrophage production of
ü Airflow limitation, the major physiologic change in COPD, can result proinflammatory cytokines macrophage elastase (matrix
from both small airway obstruction and emphysema. such as interleukin 8 (IL-8), metalloproteinase-12 [MMP-
o Small airway narrowing can be brought about by cells, and tumor necrosis factor α 12])
mucus and fibrosis. (TNF-α); this leads to
§ activation of transforming growth factor β neutrophil recruitment.
(TGF-β) contributes to airway fibrosis, while
lack of TGF-β may contribute to parenchymal
inflammation and emphysema.

PATHOGENESIS OF EMPHYSEMA Matrix metalloproteinases and serine proteinases, most

1. Chronic exposure to cigarette smoke leads to inflammatory and
immune cell recruitment within the terminal air spaces of the
lung.
2. These inflammatory cells release elastolytic and other
proteinases that damage the extracellular matrix of the lung.
3. Structural cell death (endothelial and epithelial cells) occurs
directly through oxidant-induced cigarette smoke damage and
senescence as well as indirectly via proteolytic loss of matrix
attachment.
4. Ineffective repair of elastin and other extracellular matrix
components result in air space enlargement that defines
pulmonary emphysema.
THE ELASTASE: ANTIELASTASE HYPOTHESIS
z Elastin- the principal component of elastic fibers, is a highly stable
component of the extracellular matrix that is critical to the integrity
of the lung.
ü This hypothesis states that the balance of elastin-degrading
enzymes and their inhibitors determines the susceptibility of the
lung to destruction resulting in air space enlargement.
o This is based on a clinical observation that patients with
genetic deficiency in α1 antitrypsin (α1AT),
ü This hypothesis has remained a prevailing mechanism for the
development of emphysema
notably neutrophil elastase, work together by
degrading the inhibitor of the other, leading to lung
destruction.
» Autoimmune mechanisms may promote the progression of disease
» Antibodies have been found against elastin fragments as well; IgG
autoantibodies
» Concomitant cigarette smoke–induced loss of cilia in the airway
epithelium and impaired macrophage phagocytosis predispose to
bacterial infection with neutrophilia
CELL DEATH
ü Cigarette smoke oxidant-mediated structural cell death occurs via a
variety of mechanisms including rt801 inhibition of mammalian
target of rapamycin (mTOR)
ü Cigarette smoke impairs macrophage uptake of apoptotic cells,
limiting repair.
INEFFECTIVE REPAIR
ü ability of the adult lung to repair damaged alveoli appears limited
ü the process of septation that is responsible for alveologenesis during
lung development is unlikely to be reinitiated
PATHOLOGY
» Cigarette smoke exposure may affect the large airways, small
airways (≤2 mm diameter), and alveoli.
o changes in large airways àcough and sputum
o changes in small airways and alveoli are à physiologic
alterations.

LARGE AIRWAY

» Cigarette smoking à mucus gland enlargement and goblet cell

hyperplasia àto cough and mucus production that define chronic
bronchitis
» Goblet cells not only increase in number but in extent through the
bronchial tree
» Bronchi also undergo squamous metaplasia, predisposing to
carcinogenesis and disrupting mucociliary clearance
» Smooth-muscle hypertrophy and bronchial hyperreactivity à
airflow limitation
» Neutrophil influx à purulent sputum of upper respiratory tract
infections.

1
 SMALL AIRWAY
» major site of increased resistance in COPD is in is in airways ≤2 mm
diameter
» Characteristic cellular changes include:
o goblet cell metaplasia, with these mucus-secreting cells
replacing surfactant-secreting Clara cells
» Smooth-muscle hypertrophy
» All these abnormalities à luminal narrowing by fibrosis, excess
mucus, edema, and cellular infiltration.
» Narrowing and drop-out of small airways precede the onset of
emphysematous destruction
LUNG PARENCHYMA -
» Emphysema is characterized by destruction of gas-exchanging air
spaces
» Macrophages accumulate in respiratory bronchioles of essentially
all young smokers
» In smokers’ lavage fluid, macrophages comprise >95% of the total
cell count, and neutrophils
» T lymphocytes, particularly CD8+ cells, are also increased in the
alveolar space of smokers.
2 PATHOLOGIC TYPES OF EMPHYSEMA
1. Centriacinar emphysema
o The type most frequently associated with cigarette
smoking, is characterized by enlarged air spaces found
(initially) in association with respiratory bronchioles.
o usually most prominent in the upper lobes and superior
segments of lower lobes and is often quite focal.
2. Panacinar emphysema
o refers to abnormally large air spaces evenly distributed
within and across acinar units.
o observed in patients with α1AT deficiency, which has a
predilection for the lower lobes.
PATHOPHYSIOLOGY
ü Persistent reduction in forced expiratory flow rates is the most
typical finding in COPD
ü Increase in RV and RV/TLC ratio
ü Non- uniform of ventilation distribution
ü V/Q mismatch
AIRFLOW OBSTRUCTION c.
- Key parameters: FEV1 and FVC
- In patients with COPD;
o reduced ratio of FEV1/FVC
o reduced FEV1 seldom shows large responses to
inhaled bronchodilators
AIRFLOW OBSTRUCTION 1. Cough
- Air trapping (increased residual volume and increased ratio of
residual volume to total lung capacity) and progressive
hyperinflation (increased total lung capacity) late in the
disease.
- hyperinflation can push the diaphragm into a flattened
position with a number of adverse effects.
o First, by decreasing the zone of apposition between
the diaphragm and the abdominal wall, positive
abdominal pressure during inspiration is not applied
as effectively to the chest wall, hindering rib cage
movement and impairing inspiration.
o Second, because the muscle fibers of the flattened
diaphragm are shorter than those of a more
normally curved diaphragm, they are less capable
of generating inspiratory pressures than normal.
o Third, the flattened diaphragm (with increased
radius of curvature, r) must generate greater
tension (t) to develop the transpulmonary pressure
(p) required to produce tidal breathing. This follows
from Laplace’s law, p = 2t/r.
GAS EXCHANGE
- A partial pressure of oxygen in arterial blood Pao2 usually
remains near normal until the FEV1 is decreased to ~50%
- An elevation of arterial level of carbon dioxide (Paco2) is not
expected until the FEV1 is <25%
- Pulmonary hypertension severe enough to cause cor
pulmonale and right ventricular failure due to COPD typically
occurs in individuals who have marked decreases in FEV1
(<25% of predicted) and chronic hypoxemia (Pao2 <55
mmHg);
Non- uniform ventilation and ventilation-perfusion
mismatching are characteristic of COPD.
RISK FACTORS
Ö CIGARETTE SMOKING
- cigarette smoking intensity accounts for the higher
prevalence rates of COPD with increasing age.
- higher rate of smoking among males is the likely explanation
for the higher prevalence of COPD among males
- Pack-years of cigarette smoking is the most highly significant
predictor of FEV1 (15%)
Ö AIRWAY RESPONSIVENESS
Ö RESPIRATORY INFECTIONS
Ö OCCUPATIONAL EXPOSURES
Ö AMBIENT AIR POLLUTION
ND
Ö PASSIVE OR 2 - HAND SMOKING EXPSOURE
GENETIC CONSIDERATION
z α1 Antitrypsin Deficiency
- M allele is associated with normal α1AT levels
- S allele, associated with slightly reduced α1AT levels,
- Z allele, associated with markedly reduced α1AT levels
Z
« Pi , with 2 Z alleles or 1 Z and 1 null allele which is the most
common form of severe α1AT deficiency.
NATURAL HISTORY
- The effects of cigarette smoking on pulmonary function
appear to depend on the:
a. intensity of smoking exposure,
b. the timing of smoking exposure during growth, and
the baseline lung function of the individual
- The risk of eventual mortality from COPD is closely associated
with reduced levels of FEV1
CLINICAL PRESENTATION
HISTORY
- The three most common symptoms in COPD are:
2. Sputum production, and
3. Exertional dyspnea
- As COPD advances, the principal feature is worsening dyspnea
on exertion with increasing intrusion on the ability to perform
vocational or avocational activities.
- In the most advanced stages, patients are breathless doing
simple activities of daily living.
PHYSICAL FINDINGS
- Prolonged expiratory phase
o Expiratory wheezing
- Signs of hyperinflation:
o barrel chest
o enlarged lung volumes with poor diaphragmatic
excursion
- Severe airflow obstruction
o use of accessory muscles of respiration
o sitting in the characteristic “tripod” position to
facilitate the actions of the sternocleidomastoid,
scalene, and intercostal muscles.
- Cyanosis
- Emphysema: pink puffers
2
 - Bronchitis: blue- bloaters
- Advanced disease:
o cachexia, with significant weight loss, bitemporal
wasting, and diffuse loss of subcutaneous adipose
tissue
o paradoxical inward movement of the rib cage with
inspiration (Hoover’s sign), the result of alteration of
the vector of diaphragmatic contraction on the rib
cage as a result of chronic hyperinflation.
- Signs of overt right heart failure, termed cor pulmonale
- Clubbing of the digits is NOT a sign of COPD
LABORATORY FINDINGS
z Airflow obstruction- hallmark of COPD
ü reduction in FEV1 and FEV1/FVC
ü Advanced dse: lung volumes may increase, resulting in an
increase in TLC, FRC, and RV
ü degree of airflow obstruction is an important prognostic factor
in COPD and is the basis for the Global Initiative for Lung
Disease (GOLD) severity classification
o chronic use of oral glucocorticoids is associated
with significant side effects, including osteoporosis,
weight gain, cataracts, glucose intolerance, and
increased risk of infection.
g. Theophylline
o Provides modest improvements in expiratory flow
rates and vital capacity and a slight improvement in
arterial oxygen and carbon dioxide levels in patients
with moderate to severe COPD.
o Most common SE: nausea
h. Antibiotics
o Azithromycin
i. Oxygen
o Supplemental O2 is the only pharmacologic therapy
demonstrated to unequivocally decrease mortality
rates in patients with COPD
EXACERBATIONS OF COPD
» Exacerbations are a prominent feature of the natural history
of COPD
» Exacerbations are episodes of increased dyspnea and cough
and change in the amount and character of sputum.
» An approach to the patient experiencing an exacerbation
includes an assessment of the severity of the patient’s illness,
both acute and chronic components; an attempt to identify
the precipitant of the exacerbation; and the institution of
therapy.
» Bronchodilators- for acute exacerbations

z ABG
ü Hypoxemia
ü Change in pH with Pco2 is 0.08 units/10 mmHg acutely and
0.03 units/10 mmHg in the chronic state
ü An elevated hematocrit suggests the presence of chronic
hypoxemia, as does the presence of signs of right ventricular
hypertrophy.
z Radiographic studies
ü may assist in the classification of the type of COPD
ü Obvious bullae, paucity of parenchymal markings, or
hyper- lucency à emphysema
ü Increased lung volumes and flattening of the diaphragm
suggest hyperinflation
ü Computed tomography (CT) scan is the current definitive
test for establishing the presence or absence of
emphysema in living subjects

TREATMENT
z STABLE PHASE COPD
ü Only three interventions—smoking cessation, oxygen therapy
in chronically hypoxemic patients, and lung volume reduction
surgery in selected patients with emphysema
z PHARMACOTHERAPY
a. Smoking Cessation- three principal pharmacologic approaches
to the problem:
o bupropion
o nicotine replacement therapy available as gum,
transdermal patch, lozenge, inhaler, and nasal
spray;
o varenicline, a nicotinic acid receptor
agonist/antagonist.
b. Bronchodilators- inhales route is preferred
c. Anticholinergic agents
o Ipratropium bromide improves symptoms and
produces acute improvement in FEV1
o Tiotropium- long- acting anticholinergic, improve
symptoms and reduce exacerbation
d. Beta- agonists
o Provides symptomatic benefit
o Main SE: tremor and tachycardia
e. Inhaled Glucocorticoids
o reduces exacerbation frequency by ~25%
f. Oral Glucocorticoids