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 in-flated 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 TermAnatomic

Site Major Pathologic Changes Etiology

Signs/Symptom

sChronic 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

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EXTRINSIC ASTHMA

• Type I (IgE) hypersensitivity reaction to extrinsic antigen

• 3 types:– Atopic Asthma (allergic)– Occupational Asthma (many types)– Allergic bronchopulmonary aspergillosis

Atopic Asthma

• 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

• 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

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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

• 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

– 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)

• Involves Central (Proximal) Parts of Acini (Resp Bronchioles)Involves Central (Proximal) Parts of Acini (Resp Bronchioles)• Localized in Upper Lobes, Especially Apical SegmentsLocalized in Upper Lobes, Especially Apical Segments• Black Pigment Often Seen Around Emphysematous SpacesBlack Pigment Often Seen Around Emphysematous Spaces• Etiology: Smoking and PollutionEtiology: Smoking and Pollution• More Common in Males More Common in Males • Resembles Coal Worker's PneumoconiosisResembles 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

• 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

• 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 • 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

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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 EMPHYSEMAAge 40-45 50-75Dyspnea mild, late severe, earlyAppearance Blue Bloater Pink PufferCough early lateSputum copious scantInfections common occasionalResp Insuff repeated terminalCor Pulmonale common rare, terminalAirway Resist increased normal, slt increaseElastic Recoilnormal decreasedRadiology large heart small heart

large vessels hyper-inflated lungsflat 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

• 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

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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