OBSTRUCTIVE DISEASES. Causes of airway narrowing Loss of tethering Airway smooth muscle constriction Airway plugging (mucous, foreign body) Airway edema.

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 washing itself aerosolizes allergen

www.tiedye.com/cats.htm

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