OBSTRUCTIVE DISEASES. Causes of airway narrowing Loss of tethering Airway smooth muscle constriction Airway plugging (mucous, foreign body) Airway edema.
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OBSTRUCTIVE DISEASES
Causes of airway narrowing•Loss of tethering•Airway smooth muscle constriction•Airway plugging (mucous, foreign body)•Airway edema
Normal
Emphysema
Causes of airway narrowing•Loss of tethering•Airway smooth muscle constriction•Airway plugging (mucous, foreign body)•Airway edema
Air
Smooth Muscle Cell
Epithelial Cell
Causes of airway narrowing•Loss of tethering•Airway smooth muscle constriction•Airway plugging (mucous, foreign body)•Airway edema
Mucus filling the airway lumen in asthma
Causes of airway narrowing•Loss of tethering•Airway smooth muscle constriction•Airway plugging (mucous, foreign body)•Airway edema
Normal
Airway Edema
Measuring airway obstruction
time (sec)
0 1 2 3
Vol
ume
(L)
normal
airway obstruction
start expiring
FEV1.0
FVC
AIRWAY OBSTRUCTION: FEV1/FVC < 80%
Vol
ume
(L)
0
time (seconds)
FRC TLC
RV
VC
VT
Normal values for lung volume depend on:
•Age •Sex •Height•Race•Weight (for some subdivisions of lung volume)
DEFINITION OF ASTHMA
1. Reversible Airway Narrowing
2. Increased Airway Responsiveness
3. Airway Inflammation
(History of Allergy)
Air
Smooth Muscle Cell
Epithelial Cell
Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S
MUCOUS HYPERSECRETION IN ASTHMA
DEFINITION OF ASTHMA
1. Reversible Airway Narrowing
2. Increased Airway Responsiveness
3. Airway Inflammation
(History of Allergy)
AIRWAY HYPERRESPONSIVENESS
DEFINITION OF ASTHMA
1. Reversible Airway Narrowing
2. Increased Airway Responsiveness
3. Airway Inflammation
(History of Allergy)
Th2-lymphocytes
• promotes IgE formation (IL-4, IL-13)• promotes eosinophil migration (IL-5)
• promotes contraction of smooth muscle• promotes recruitment of more eosinophils
Eosinophil
van den Toorn et al, Am. J. Respir. Crit. Care Med. 2001 164: 2107-2113
Normal
Asthma
Major Basic ProteinStaining (eosinophils)
Symptoms of Asthma:
• cough
• shortness of breath
• chest tightness
• wheezing
HISTOLOGICAL FEATURES OF ASTHMA
•Subepithelial fibrosis•Mucous cell hyperplasia•Smooth muscle hypertrophy•Increased vascularity
Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S
BASEMENT MEMBRANE THICKENING IN ASTHMA
Ordonez et al, Am. J. Respir. Crit. Care Med. 2001 163: 517-523
INCREASED MUCOUS PRODUCING CELLS(blue purple stain)
Normal Asthma
Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S
MUCOUS HYPERSECRETION IN ASTHMA
Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S
AIRWAY SMOOTH MUSCLE HYPERTROPHY IN ASTHMA
Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S
INCREASED AIRWAY VASCULARITY IN ASTHMA
Pulmonary Function
•Total lung capacity is usually normal, but the FRC is elevated and RV is increased
•Decreased FEV1/FVC ratio
•Lung stiffness is usually normal or low
•Airway obstruction is due to smooth muscle constriction and mucus hypersecretion
time (sec)
0 1 2 3
Vol
ume
(L)
normal
airway obstruction
start expiring
FEV1.0
FVC
AIRWAY OBSTRUCTION: FEV1/FVC < 80%
Vol
ume
(L)
0
time (seconds)
FRC TLC
RV
VC
VT
asthma
Blood gases
•PaO2 - low because of mismatch of ventilation and perfusion
•PaCO2 •often low (hyperventilation due to anxiety)•if PaCO2 increases it’s usually a sign that respiratory failure is approaching (patient needs to be ventilated)
Epidemiology of Asthma
• currently affects 5-10% of US population
• incidence and severity are increasing
• mortality has plateaued•Still relatively rare
• highest in industrialized countries•Higher in urban than rural areas
ASTHMA AND CHILDREN
•Leading serious chronic illness among children
•Since 1980, prevalence has doubled
•Leading chronic cause of lost school days
•Highest ranked cause of pediatric hospitalizations
•Death from asthma still rare in children
•In 2000, 9 million US children had a diagnosis of asthma-higher in males than females (gender bias switches in adults)-Higher in African Americans than in Caucasians or Hispanics-Higher in low income than high income families
Asthma PrevalenceUnited States, 1980-2004
0
2
4
6
8
10
12
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004 Year
Pre
vale
nce
(%
)
Source: National Health Interview Survey; National Center for Health Statistics
12-Month
Lifetime
Attack
Current
IgE
Allergen
Chemicals released:
Mast cell
• histamine• leukotrienes• proteases• cytokines (IL-4, IL-5)
Smooth Muscle CellMast Cell(releases chemicals)
(contracts)
Time (hours)Allergen 1 2 3 4 5 6 7 8
100
90
80
70
60
FE
V1.
0 (%
bas
elin
e)EarlyResponse
LateResponse
Mast Cell
White blood cells
Mast Cell
Smooth Muscle Cell
Time (hours)Allergen 1 2 3 4 5 6 7 8
100
90
80
70
60
FE
V1.
0 (%
bas
elin
e)EarlyResponse
LateResponse
MOST IMPORTANT ALLERGENS IN THE US
•Cat•House dust•Cockroach•Mold
Cat being washed – helps reduce allergen exposure(recommended 2X/week)
www.dkimages.com/.../Cat-Care/Cat-Care-054.html
100 m
House Dust Mite - Dermatophagoides sp.
The average pillow is home to 10,000 of these!
Avoiding exposure to dust mite allergens
•Encase pillows and mattresses
•Use HOT (>130oC) water to wash bedding and clothes
•Reduce carpeting (in particular wall to wall carpeting, which cannot be adequately cleaned)
•Reduce humidity (mites are dependent on water in the air for their water supply)
•Avoid fabric coverings on furniture and windows
Platts-Mills et al, J Allergy Clin Immunol. 2000 Nov;106(5):787-804
The American cockroach
•A particular problem in low income housing•Insects move from one apartment to another
Mold
TRIGGERS FOR ASTHMA
• allergen exposure• exercise• breathing cold dry air• viral infections• irritants (ex: ozone)• occupational exposure to dust or fumes
PREVENTION AND TREATMENT OF ASTHMA
• Medications
• Education
• Allergen Avoidance
ASTHMA THERAPY
1. -agonists2. Corticosteroids3. Leukotriene antagonists and inhibitors4. Anti-IgE
-agonists
•Mimic adrenalin•Relax smooth muscle•Effects are immediate but not sustained•Provide symptom relief, but do not remove the underlying causes
before after before after
High resolution CT scans of airways before and after a -agonist
New England Journal of Medicine 352:15, 2005
FEV1 Before: 1.27 L After: 1.76 L
Corticosteroids:
•Reduce inflammation•Improve lung function and symptoms •Decrease airway hyperresponsiveness•Reduce exacerbations•Must be taken regularly regardless of symptoms•Not immediately effective
cme.med.harvard.edu/syl/fanta.html
Actions of Leukotrienes•Very potent constrictors of airway smooth muscle •Mucus hypersecretion •Edema formation •Eosinophil chemoattraction
Leukotriene synthesis inhibitors and receptor antagonists
•Prevent synthesis or effects of leukotrienes
cme.med.harvard.edu/syl/fanta.html
•Reduces corticosteroid requirements•Reduces symptom scores•Reduces rescue medication use•Improves lung function•Reduces exacerbations
Anti-IgE therapy also:Fahy et al. AJRCCM 1997 155:1828
Genes
Environment
Asthma
WHAT CAUSES ASTHMA?
-exposure to allergens -pollution-cigarette smoke-viruses
Genes
Environment
Asthma
- cytokines- genes that regulate IgE levels- others
From: Camargo et al, Arch Intern Med 159:2582-2588, 1999
New Engl J Med 343:538-543, 200
From: McCreanor et al, N Engl J Med 357:2348-2358, 2007
Only diesel powered buses and taxis are allowed on Oxford St.
Subjects walked for 2 hours on Oxford St (closed symbols)(very busy shopping district) or in Hyde Park
Asthma disparities
Issues to consider•Access to health care/medication•Allergen exposure•Obesity•Smoking•Air pollution•Stress (poverty, violence, crowding)
COPD – chronic obstructive pulmonary disease
•4th leading cause of death in the US•2nd leading cause of disability•Smokers disease•Consists of 2 diseases (many have both)
- emphysema- chronic bronchitis
Other consequences of smoking
•Heart disease•Stroke •Cancer
Ris
k o
f er
ecti
le d
ysfu
nc
tio
n
Smoking increases the risk of erectile dysfunction
From: He, J.,et al Am J Epidemiol. 2007
Consequences of passive smoking in children
•Lower birth weight in children of mothers who smoke
•Lower lung size in children of parents who smoke
•Increased incidence of asthma, bronchitis, and pneumoniain children of parents who smoke
SMOKING FACTS AND FIGURES
Most important source of preventable morbidity and mortality•30% of coronary artery disease deaths•30% of cancer deaths (lung, larynx, oral, esophageal, bladder)•More ulcers•More periodontal disease
Responsible for ¼ of all fire related deaths (leading cause)
On average, 5.5 minutes of life lost for each cigarette•4.6 years for a 25 year old who smokes 1pack/day
From the US Department of Health and Human Services, 2003
Smoking is the leading cause of preventable death in the US
Year
45 50 55 60 65 70 75
age
adju
sted
mo
rtal
ity
rate
s(p
er 1
00,0
00)
1
10
Men Women
Consequences of passive smoking in children
•Lower birth weight in children of mothers who smoke
•Lower lung size in children of parents who smoke
•Increased incidence of asthma, bronchitis, and pneumoniain children of parents who smoke
Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S
EMPHYSEMA
Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S
Emphysema - uniform
Normal male lung
Mucous gland hypertrophy in chronic bronchitis
Pressure
Volume
Healthy
Lung Pressure Volume Curves
Emphysema
Mucous gland hypertrophy in chronic bronchitis
ETIOLOGY
Cigarette smoke (particles and chemicals)
Inflammation
Influx of activation of neutrophils and macrophages• release of proteases• release of oxygen radicals• release of inflammatory mediators
Destruction of lung tissue
Production of mucous
Airway remodeling
Special Case – 1-antitrypsin deficiency
•Caused by a mutation in the gene coding for this enzyme
•Results in inability of liver cells to secrete the enzyme intothe blood
•Patients have low levels of this enzyme in serum andin lung lavage fluid
•Results in early onset emphysema (age 30-40) particularlyif the patients smoke
Signs and Symptoms
Emphysema•Dyspnea at rest•Thin•Barrel chest•Wheeze on expiration
Chronic Bronchitis•Cough •Sputum•No dyspnea at rest but does occur with exertion•Cyanosis•Frequent respiratory infections•Pops and rales
Pulmonary Function
Emphysema•Increased TLC, RV, FRC•Decreased FEV1/FVC•Low elastic recoil•Airway closure•Uneven ventilation and perfusion•Airway obstruction due to loss of elastic recoil
Chronic Bronchitis•Normal TLC, increased RV, FRC•Decreased FEV1/FVC•Elastic recoil usually normal•Airway closure•Uneven ventilation•Airway obstruction due to mucus plugging, airway edema,•Smooth muscle constriction
FE
V1
(% o
f va
lue
at a
ge
25)
Age (years)
Never smoked orNot susceptible
Smoked regularlyAnd susceptible
Stopped at 45
Stopped at 65disability
death
25 50 75
Evidence for genetic susceptibility for COPD
• Familial association of low FEV1.0
• Linkage analysis studies• Genes associated with COPD susceptibility
1. 1-antitrypsin (anti-protease)2. microsomal epoxide hydrolase (degradation of chemicals in smoke) 3. glutathione-S-transferases (degradation of chemicals in smoke) 4. Hemeoxygenase 1 (antioxidant)5. TNF(inflammation)
Blood gases
Emphysema•PaO2 is low but not very low
cause: V/Q mismatch•“pink puffers” - increase ventilation to keep bloodgases normal•PaCO2 is normal
Chronic Bronchitis•PaO2 usually very low
cause: V/Q mismatch and hypoventilation•“blue bloaters” – do not increase ventilation tokeep blood gases normal•PaCO2 is high
Chronicbronchitis
Normal
Consequences of low PaO2
1) Polycythemia – increased numbers of red blood cells (RBC’s)
Low PaO2
Increased erythropoetin release from kidney
Acts of bone marrow to increased production of RBC’s
2) Right heart hypertrophy (cor pulmonale)
•Due to pulmonary hypertension (hypoxic vasocontrictionand loss of capillary bed)
•Can lead to right heart failure and death
Cyanosis
•Occurs when deoxygenated hemoglobinexceeds 5 g/100 ml
typical total hemoglobin is 15 g/100 ml
•Low PaO2 and increased numbers of redblood cells both contribute to cyanosis in chronic bronchitis
Treatment
•Smoking cessation – prevents further loss of lung function
•Bronchodilators, particularly anticholinergics
•Increasing use of corticosteroids – data are not yet inregarding efficacy
•Lung reduction surgery – not usually recommended
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