Transcript garon-obstructive_lung_disease_2012

Obstructive Lung Disease
OBSTRUCTIVE LUNG DISEASE
• Diseases Characterized by Increased Resistance to Air
Flow Due to Partial or Complete Obstruction at Any Level.
• PFT: TLC Normal to Increased, Decreased Expiratory
Flow Rate
• Two Categories
– Tumors and Foreign Bodies
– Lung Diseases: Emphysema, Chronic Bronchitis,
Bronchiectasis, Asthma
RESTRICTIVE LUNG DISEASE:
• Characterized by Reduced Expansion of Lung
Parenchyma
Accompanied by Decreased Total Lung Capacity.
• PFT: TLC Reduced, Expiratory Flow Rate Normal
• Two Categories:
– Chest Wall Disorders With Normal Lungs
(Polio, Obesity, Pleural Diseases)
– Interstitial Lung Diseases
(ARDS, Pneumoconioses, Sarcoidosis)
Atelectasis
Atelectasis refers either to
incomplete expansion of the
lungs (neonatal atelectasis) or to
the collapse of previously inflated lung, producing areas of
relatively airless pulmonary
parenchyma
• reduces oxygenation
• predisposes to infection
Not COPD
• Compensatory Hyperinflation (Emphysema): dilation of
alveoli but not destruction of septal walls in response to loss of
lung substance elsewhere.
– E.g hyperexpansion of remaining lung after lobectomy or
pneumonectomy.
• Obstructive Overinflation: lung expands because air is
trapped within it.
– E.g subtotal obstruction by a tumor or foreign object.
– e.g. congenital lobar overinflation in infants, probably resulting from
hypoplasia of bronchial cartilage and sometimes associated with
other congenital cardiac and lung abnormalities.
– (1) because of a ball-valve action of the obstructive agent,
– (2) ventilation through collaterals may bring in air from behind total
obstruction.
• pores of Kohn and other direct accessory bronchioloalveolar
connections (the canals of Lambert).
• Obstructive overinflation can be a life-threatening emergency
– Hyperinflated lung compresses the remaining normal lung.
Obstructive Pulmonary Diseases
Clinical Term
Anatomic
Site
Major Pathologic Changes
Etiology
Signs/Sy
mptoms
Chronic
bronchitis
Bronchus
Mucous gland hyperplasia,
hypersecretion
Tobacco smoke,
air pollutants
Cough,
sputum
production
Bronchiectasis
Bronchus
Airway dilation and scarring
Persistent or
severe
infections
Cough,
purulent
sputum,
fever
Asthma
Bronchus
Smooth muscle hyperplasia, excess
mucus, inflammation
Immunologic or
undefined
causes
Episodic
wheezing,
cough,
dyspnea
Emphysema
Acinus
Airspace enlargement; wall
destruction
Tobacco smoke
Dyspnea
Small airway
disease,*
bronchiolitis
Bronchiole Inflammatory scarring/obliteration
Tobacco smoke,
air pollutants,
miscellaneous
Cough,
dyspnea
ASTHMA
• Episodic Reversible Bronchoconstriction
Resulting From Increased Responsiveness of
the Tracheobronchial Tree to Various Stimuli
• Sudden Onset Severe Dyspnea
– Often at night or early AM
• Wheezing
• Cough, Chest tightness
• Common Disease
– 5% Adults
– 7-10% Children
– Incidence Increasing
• Etiology: Chronic Inflammatory Disease
– Inflammation causes hyper-responsiveness
Asthma Triad
• Intermittent and Reversible airway
obstruction
• Chronic Bronchial Inflammation with
Eosinophils
• Bronchial Smooth Muscle Cell
Hypertrophy and Hyperactivity
2012
EXTRINSIC ASTHMA
• Type I (IgE) hypersensitivity reaction to
extrinsic antigen
• 3 types:
– Atopic Asthma (allergic)
– Occupational Asthma (many types)
– Allergic bronchopulmonary aspergillosis
Atopic Asthma
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Most Common Type
Triggered by environmental Allergens
Onset First 2 Decades
Family History of Atopy
Associated with allergic rhinitis, urticaria, and
eczema
• IgE Levels Elevated
• Eosinophilia Common
• Type 1 (Wheal and Flare) Reaction to antigen
INTRINSIC ASTHMA
• Non-immune Triggering Mechanisms
– Aspirin Sensitivity
– Pulmonary Infections (Viral)
– Cold
– Psychologic Stress
– Exercise
– Inhaled Irritants Like SO2
People With Extrinsic Asthma Are
Susceptible Intrinsic Asthma Triggers
Underlying Molecular Bases
• TH cell imbalance due to loss of
transcription factor t-bet
– Leading to TH2 predominance
• ADAM-33 polymorphisms
TH Cell Imbalance
• Normal Feedback Loop
– interferon-γ from TH1 cells inhibits TH2
cells
– interleukin-4 from TH2 cells inhibits TH1
cells.
– lymphocytes from asthmatics lack T-bet, a
transcription factor required for the
production of interferon-γ(IFN-γ)
• TH2 Cells are unregulated
– TH2 cells trigger inflammation
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Adam-33 Gene
• ADAM-33 is a metalloproteinases
– Related to matrix metalloproteinases (MMPs) such as collagenases
– Expressed by lung fibroblasts and bronchial smooth muscle
– It is speculated that ADAM-33 polymorphisms accelerate
proliferation of bronchial smooth muscle cells and fibroblasts, thus
contributing to bronchial hyperreactivity and subepithelial fibrosis.
• Mast cells contribute to airway remodeling.
– Asthma have infiltration of smooth muscle cells by mast cells.
– IgE Triggers mast cells
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Vasoactive mediators and cytokines
Growth factors such as PDGF
Proteases
Trigger smooth muscle proliferation.
• Activated smooth muscle cells secrete stem cell factor
– Chemoattractant and growth factor for mast cells.
Sensitization
• (Before asthmatic reaction)
• Sensitization to inhaled allergen
– Induces TH2 cells
– IL-4 & IL-5 released
– synthesis of IgE antibodies
– IgE binds to mast cells
2012
Acute or Immediate Phase
30-60 minutes after exposure
• Antigen Cross Links IgE on Mast Cells
• Primary Mediators Released
– Histamine
• Eosinphil and Neutrophil Chemotactic Factors
– Leukotriene B4
• Antigens Enter Mucosa
• Activate mast cells and eosinophils
– Secondary Mediators are released
• Leukotriene C4,D4,E
• Prostoglandin D2
• Platelet Activating Factor (PAF)
– Vagal Stimulation
Late Phase 4-8 hours later
• Mediated by Recruited Cells
– Basophils
– Neutrophils
– Eosinophils
• Eosinophils Release Mediators
– PAF, Leukotriene C4
– Major Basic Protein
– Eosinophil Cationic Protein (ECP)
• MBP and ECP Damage Epithelial Cells
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Non-Atopic Asthma
• Viral Infections
– ?Lower threshold of vagal receptors to
irritants
• Inhaled Pollutants
ASTHMA HISTOLOGY
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Hyperplasia of Mucous Glands
Hypertrophy of Bronchial Smooth Muscle
Apparent Thickening of Basement Membrane
Hyperplasia of Mucosal Goblet Cells
Bronchial Edema and Inflammation,
With Eosinophils (up To-50% of Cells)
• Patchy Necrosis of Epithelial Cells
• Intraluminal Mucus Plugs Containing:
– Curshmann's Spirals
– Charcot-Leyden Crystals
Airway Remodelling
• May precede onset of symptoms
• Therefore, may be cause rather than
2ndary changes
Asthma Clinical Course
• Acute Attack May Be Fatal
• Status Asthmaticus
• Increased Risk of COPD in Adults
Asthma Mediators and Treatment
• Treatment Responsive
– Leukotrienes C4, D4, and E4, cause prolonged
bronchoconstriction, increased vascular permeability and
increased mucus secretion
• Montelukast blocks binding of leukotrienes
– Acetylcholine, released from intrapulmonary motor nerves,
which can cause airway smooth muscle constriction by
directly stimulating muscarinic receptors. (Atrovent)
• Present but Unresponsive to Rx
– (1) histamine, a potent bronchoconstrictor
– (2) prostaglandin D2 (PGD2), which elicits
bronchoconstriction and vasodilation
– (3) PAF, which causes aggregation of platelets and release of
histamine and serotonin from their granules.
• Insufficiently Studied or No Inhibitor Available
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IL-1, TNF, and IL-6
Chemokines (e.g., eotaxin)
Nitric Oxide
Bradykinin, and endothelins.
CHRONIC OBSTRUCTIVE PULMONARY
DISEASES (COPD)
• Chronic Obstructive Lung Diseases
• Persisting and Irreversible Air Flow Obstruction
(Physiologic Definition)
• Includes Chronic Bronchitis and Emphysema
EMPHYSEMA
• Abnormal Permanent Enlargement of the Air
Spaces Distal to the Terminal Bronchioles,
Accompanied by Destruction of Their Walls.
(Morphologic Definition).
• 3.2% Deaths due to Emphysema
– 65% men and 25% women have centrilobular
emphysema at Autopsy
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CENTRIACINAR (CENTRILOBULAR
EMPHYSEMA)
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Involves Central (Proximal) Parts of Acini (Resp Bronchioles)
Localized in Upper Lobes, Especially Apical Segments
Black Pigment Often Seen Around Emphysematous Spaces
Etiology: Smoking and Pollution
More Common in Males
Resembles Coal Worker's Pneumoconiosis
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Centrilobular Emphysema
Centilobular Emphysema
Centriacinar emphysema.
Central areas show marked
emphysematous damage (E),
surrounded by relatively
spared alveolar spaces
Panacinar emphysema
involving the entire pulmonary
architecture.
PANACINAR (PANLOBULAR)
EMPHYSEMA
• Acini Are Uniformly Enlarged
• Localized in Lower Lungs
• Occurs in Alpha-1-antitrypsin Deficiency
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Pan Acinar Emphysema
DISTAL ACINAR (PARASEPTAL)
EMPHYSEMA
• Distal Acinus Involved, Proximal Normal
• Localized Adjacent to Pleura, Paraseptal Connective
Tissue, Lobular Margins
• Occurs Adjacent to Fibrosis, Scars or Atelectasis
• Usually Upper Half Lungs, Limited Extent
• Multiple Contiguous Air Spaces From 0.5mm-2 Cm
• Sometimes Form Bullae (Large Cyst-like Spaces)
• Causes Spontaneous Pneumothorax in Young Adults
Bullous Emphysema
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Any Emphysema with Blebs or Bullae
Spaces Larger than 1 cm Diameter
Bullae are usually sub-pleural
Prone to Rupture
– Causes Spontaneous Pneumothorax
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Bullous Emphysema
Bullous Emphysesma
Alpha-1-Antitrypsin (AAT) Deficiency
• AAT: Enzyme Present in Serum and Macrophages,
– Inhibits Proteases and Elastases (Secreted by
Polys)
• Chromosome 14, Protease Inhibitor (Pi) Locus,
– Codominant Gene, 80 Different Alleles
– PiMM: Normal
– PiZZ: Marked Decrease AAT, .012% Population
• Marked Tendency to Develop Emphysema
• About 2% of Emphysematous Patients
• Stimuli Cause Elastase Release
• Elastic Tissue Destruction Goes Unchecked
• Emphysema Results
– PiMZ Heterozygotes Have Intermediate Enzyme
Levels
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EMPHYSEMA HISTOLOGY
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Abnormal Enlargement of Air Spaces
Thinning and Destruction of Septal Walls
Compression of Septal Capillaries
Accumulation of Carbon-laden Macrophages Near
Small Airways
• +/- Bronchiolitis of Term and Resp Bronchioles
Emphysema Clinical Course
• Insidious Progression
• Dyspnea when 1/3 parenchyma lost
– Dyspnea is Progressive
• “Pink Puffer” Stereotype
– Barrel-chested, cachectic, enabling accessory
muscles
– Hyperventillation and Dyspnea
– Blood Gases relatively Good
• Prognosis: Death by Pulmonary Failure
• Complications (less common)
– Pulmonary Hypertension, Cor Pulmonale
COR PULMONALE
PULMONARY HEART DISEASE
• Right Ventricular Enlargement Secondary to
Pulmonary Hypertension Caused by
Disorders That Affect Lung Structure or
Function
CHRONIC BRONCHITIS
• Persistent, Productive Cough for at Least
Three Consecutive Months in at Least
Two Consecutive Years (Clinical Definition)
• Often Co-exists With Emphysema
• 5 – 15% Smokers Develop COPD
CHRONIC BRONCHITIS HISTOLOGY
• Hypertrophy of Mucus Secreting Glands Bronchi
– Reid Index: Ratio of Thickness of Mucous Gland
Layer to Bronchial Wall
• Normal 1:3 Chronic Bronchitis >1:2
• Increased Goblet Cells
• Chronic Inflammation and Fibrosis (Chronic
Bronchiolitis)
• Squamous Metaplasia and Dysplasia
• Acute Inflammation May Be Superimposed
Chronic Bronchitis Pathophysiology
• Cigarette Smoke or Pollutants
• Mediated by epidermal growth factor (EGF)
receptor
– Transcription of the mucin gene MUC 5AC, is
increased by tobacco smoke
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Sulphur and Nitrogen Dioxides
Hypersecretion of Bronchial Mucosa Glands
Hypertrophy of Mucus Glands
Goblet Cell Metaplasia
Infection
Airflow Obstruction in Chronic
Bronchitis
• Chronic Bronchiolitis
• Coexistent Emphysema
2012
Chronic Bronchitis Clinical Course
• Presents with Productive Cough
• May progress to COPD
• “Blue Bloater” Stereotype
– Obese, Edematous male in CHF
– Hypoxic and Cyanotic with Increased CO2
– Relatively Poor Respiratory Drive
• Cause of Death
– Cardiac Failure (Cor Pulmonale)
– Recurrent Infections
– Rarely Respiratory Failure
COR PULMONALE
PULMONARY HEART DISEASE
• Right Ventricular Enlargement Secondary to
Pulmonary Hypertension Caused by
Disorders That Affect Lung Structure or
Function
CHARACTERISTIC BRONCHITIS
Age
40-45
Dyspnea
mild, late
Appearance
Blue Bloater
Cough
early
Sputum
copious
Infections
common
Resp Insuff
repeated
Cor Pulmonale
common
Airway Resist
increased
Elastic Recoil
normal
Radiology
large heart
large vessels
EMPHYSEMA
50-75
severe, early
Pink Puffer
late
scant
occasional
terminal
rare, terminal
normal, slt increase
decreased
small heart
hyper-inflated lungs
flat diaphragm
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BRONCHIECTASIS
• Permanent Dilation of Bronchi and Bronchioles
• Due to Destruction of Muscle and Elastic Supporting
Tissue
• Associated With Chronic Necrotizing Infections
• Secondary Condition Due to a Variety of Etiologies
• Occurs at Any Age, Especially Children
BRONCHIECTASIS CAUSES
• Bronchial Obstruction (Tumor or Foreign Body)
• Congenital or Hereditary Conditions
– Cystic Fibrosis
– Immotile Cilia and Kartagener's Syndromes
– Immunodeficiency States
• Necrotizing or Suppurative Pneumonia
– In Past and Overseas, Secondary Infections After
Measles, Whooping Cough and Influenza
• Occurs at any age, Especially Children
Bronchiectasis Gross in Child
Bronchiectasis Gross
Bronchiectasis Gross
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BRONCHIECTASIS HISTOLOGY
• Acute and Chronic Inflammation in Walls of Bronchi
and Bronchioles
• Desquamation of Lining Epithelium and Necrotizing
Ulceration
• Squamous Metaplasia and Dysplasia
• Necrosis and Abscess Formation May Occur
• Fibrosis Occurs With Chronicity
• Acute Inflammation Correlates With Acute
Exacerbation
IMMOTILE CILIA SYNDROME
(KARTAGENER'S SYNDROME)
• Triad: Bronchiectasis, Sinusitis, and Situ Inversus
• Autosomal Recessive Trait
• Defective Ciliary Motility
– Absent or Irregular Dynein Arms
• Clinical Features
– 1) Poor Bacterial Clearance
– 2) Male Infertility Due to Sperm Immotility
– 3) Poor Cell Motility During Embryogenesis,
Causing Situs Inversus
CYSTIC FIBROSIS
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Autosomal Recessive Gene (CF Gene) on 7th Chromosome
Membrane Associated Protein That Serves As Cl- Channels
Lungs, Increases Na in Blood, Lowering H2O in Secretions
Viscid Mucus Plugs Small Airways
Bronchiectasis
Respiratory Infections
• Staph Aureus
• Pseudomonas Aurginosa
• Chronic Bronchitis and Lung Abscess
The
End!
CYSTIC FIBROSIS (MUCOVISCIDOSIS)
• Genetic Disorder of Exocrine Glands
Affecting Both Mucus Secreting and Eccrine
Sweat Glands Throughout the Body
• 1/2000 Live Births, Gene Frequency 1/20
• Most Common Lethal Genetic Disease of
Caucasians
• Rare in Blacks and Asians
• Exocrine Glands effected
• Chronic Recurrent Pulmonary Infections
• Pancreatic Insufficiency
• High sweat NaCl level
Cystic Fibrosis Lungs
• Viscid Mucus Plugs Small Airways
• Bronchiectasis
• Respiratory Infections
• Staph Aureus
• Pseudomonas Aurginosa
• Chronic Bronchitis and Lung Abscess