COPD

The conditions that most commonly predispose to bronchiectasis include:

1. Inflammatory: - Necrotizing/Suppurative Pneumonia (S. aureus, Klebsiella) - Chronic bronchitis - Tuberculosis 2. Bronchial obstruction: - Foreign body - Tumor - Mucus plug *in this, the bronchiectasis is localized to the obstructed lung segment 3. Genetic: - Cystic fibrosis - Ciliary dyskinesis (Kartagener syndrome) - Immunodeficiency state (immunoglobulin deficiencies) = susceptible to bacterial infxn

PiMM

(normal) is the most common genotype

Patients at risk for Interstitial Edema

- COPD patients (combination of coughing and bronchiolar obstruction produces sharply increased pressures within the alveolar sacs) - Children with whooping cough and bronchitis - Patients with airway obstruction by blood clots or foreign bodies - Artificially ventilated patients (premature infants and neonates with hyaline membrane disease have a particularly high risk because of their delicate lung structure)

COMPRESSION ATELECTASIS

- Fluid, tumor, air in pleural cavity (tension pneumothorax) - frequent occurrence with pleural effusion, caused most commonly by congestive heart failure (CHF). Leakage of air into the pleural cavity (pneumothorax) also leads to compression atelectasis. - Abnormal elevation of diaphragm - Mediastinum shifts AWAY from the affected lung - Reversible

another way to look at the pathogenesis of emphysema

- Nicotine from smoke essentially causes the production of ROS free radicals - IL8 and other inflamm cytokines increase - Neutrophils move out of vessels into alveolar wall and so the neutrophils also produce ROS - Neutrophils produce elastase which dissolves the scleral elastin and collagen in alveolar wall - So the alv wall disappears - Normally you have inactivation of elastases and proteases by AAT, but if that's not functional (due to oxidants from smoking), the destruction will continue - Tobacco smoke inactivates the anti proteases - So you have a double whammy there if you also have congenital AAT deficiency - All this causes tissue damage - In emphysema the MMP that the macrophages produce are part and parcel of this tissue damage - MMP producing macrophages are also impt in abnormal aortic aneurysm - they contain ZINC!

Pathogenesis of Bronchiectasis

- Two processes are crucial and intertwined in the pathogen- esis of bronchiectasis: - obstruction and chronic persistent infection. - Either of these may come first. - Normal clearance mechanisms are hampered by obstruction, so secondary infection soon follows - conversely, chronic infection over time causes damage to bronchial walls, leading to weak- ening and dilation. - For example, obstruction caused by a primary lung cancer or a foreign body impairs clearance of secretions, providing a favorable substrate for superimposed infection. The resultant inflammatory damage to the bronchial wall and the accumulating exudate further distend the airways, leading to irreversible dilation. - Conversely, a persistent necrotizing inflammation in the bronchi or bron- chioles may cause obstructive secretions, inflammation throughout the wall (with peribronchial fibrosis and traction on the walls), and eventually the train of events already described.

What is Kartagener syndrome

- a rare autosomal recessive disorder - frequently associated with bronchiectasis and with sterility in males. - In this condition, structural abnormalities of the cilia impair mucociliary clearance in the airways, leading to persistent infections, and reduce the mobility of spermatozoa. - This is a primary ciliary dyskanesia - Tobaco smoke can also damage cilia! - But this is a situation a person is born wih

What is the defect in CF

- cAMP-dependent chloride channels (cystic fibrosis transmembrane conductance regulators, CFTRs) are defective - Epithelial membranes are relatively impermeable to chloride ions - Associated with a defect in the secretory process of exocrine glands - Clinical manifestations in the lung and pancreas are due to abnormally viscous secretions - High level of sodium chloride in the sweat is a consistent and characteristic biochemical abnormality in CF

Alpha 1 AT deficiency

- its not really usually a deficiency of AAT at all - AAT is formed by hepatocytes - Either a transport mechanism is defective or AAT itself is defective bc of gene problem and it cannot get out of liver - Normally you don't see granular AAT in liver cels - If you do digested PAS, you can digest glycogen etc out of there and you see alot of AAT left behind: the liver cells are LOADED with AAT - it cannot get out of the liver - Liver is loaded with this enzyme - Liver starts getting fibrotic - There is inflammation in portal area and fibrosis so you will eventually get liver damage too

Bronchiectasis due to chronic pneumonia

- see lymphoid follicles - You don't ever see lymphoid follicles in normal lung - This lymphoid tissue at the bifurcation points at the bronchi is normal but you don't see follicles! - Here is fully formed lymphoid follicle with germinal center This is not a malignant situation, no lymphoma but there is lymphoid hyperplasia in the bronchial wall due to the fact that there has been multiple repeated infections

four major types of emphysema

1) centriacinar, (2) pan- acinar, (3) distal acinar, and (4) irregular.

CHRONIC OBSTRUCTIVE PULMONARY DISEASES (COPD)

1. Chronic bronchitis 2. Bronchiolitis (small airways disease) 3. Emphysema 4. Asthma (reversible) 5. (Bronchiectasis) 6. (Cystic fibrosis

What are the 3 types of chronic bronchitis

1. Simple chronic bronchitis: o Productive cough o No airflow obstruction 2. Chronic asthmatic bronchitis: o Hyperreactive airways o Intermittent bronchospasm and wheezing o There is an overlap between asthma and chronic bronchitis bc these patients will benefit from bronchodilatoers wheras simple chronic bronchitis patients will not 1. Obstructive chronic bronchitis: o Chronic airflow obstruction o Emphysema

The CFTR gene is located on chromosome

7 (7q31-32)

ATELECTASIS

= collapse = loss of lung volume caused by inadequate expansion of air spaces. It results in shunting of inadequately oxygenated blood from pulmonary arteries into veins, thus giving rise to a ventilation- perfusion imbalance and hypoxia. On the basis of the underlying mechanism or the distribution of alveolar col- lapse, atelectasis is classified into three forms

definition of emphysema

Abnormal permanent enlargement of the air spaces distal to the terminal bronchioli accompanied by destruction of their walls

RESORPTION ATELECTASIS

An obstruction prevents air from reaching distal airways. The air already present gradually becomes absorbed, and alveolar collapse follows. - Bronchial obstruction by mucus plugs, foreign body, or endobronchial tumor - Mediastinum shifts toward the atelectasis - Reversible

what does the pancreas look like in CF

Atrophic and total fibrosis of exocrine pancreas. Scattered inflammatory cells. Preserved islets. - This is a very small fibrotic pancreas - All the exocrine pancreas has been destroyed - Some ducts left in there but normal acinar cells have disappeared

BRONCHIECTASIS

BRONCHIECTASIS

Kartagener syndrome can cause

Bronchiectasis

permanent dilation of bronchi and bronchioles caused by destruction of the muscle and the supporting elastic tissue, resulting from or associated with chronic necrotizing infections

Bronchiectasis

Age

Bronchitis = 40-45 Emphysema = older (50-75)

Appearance of patient

Bronchitis = blue bloater Emphysema= pink puffer

Presence of dyspnea

Bronchitis = mild, late Emphysema = severe, early

Presence of infections

Bronchitis= common Emphysema= occasional

Presence of cough

Bronchitis= early, copious Emphysema= late, scanty

Airway resistance

Bronchitis= increased Emphysema= normal or slightly increased

Elastic recoil

Bronchitis= normal Emphysema= decreased

Chest film

Bronchitis= prominent vessels, large heart (bc they commonly have HF) Emphysema= hyperinflation, small "teardrop" heart

Respiratory Insufficiency

Bronchitis= repeated Emphysema= terminal

CHRONIC BRONCHITIS

CHRONIC BRONCHITIS

COMPARISON OF EMPHYSEMA TO CHRONIC BRONCHITIS

COMPARISON OF EMPHYSEMA TO CHRONIC BRONCHITIS

Only ______ cause clinically significant airway obstruction, with ______ emphysema being about 20 times more common than ____ disease.

Centriacinar and panacinar emphysema centriacinar emphysema is more common than panacinar

Inflammation around bronchi and bronchioles is common

Centriacinar emphysema

The central or PROXIMAL parts of the acini, formed by *respiratory bronchioles*, are affected, while distal alveoli are spared. The respiratory bronchiolus and alveolar duct are more severely affected

Centriacinar emphysema

The lesions are more common and severe in the upper lobes, particularly in the apical segments.

Centriacinar emphysema

both emphysematous and normal air spaces exist within the same acinus and lobule

Centriacinar emphysema

large amounts of black pigment in the walls of the emphysematous spaces (macrophages that have engulfed carbon)

Centriacinar emphysema

most commonly seen as a con- sequence of cigarette smoking

Centriacinar emphysema

This clinical syndrome is accompanied by hypercapnia, hypoxemia, and (in severe cases) cyanosis

Chronic Bronchitis *With progression, chronic bronchitis is complicated by pulmonary hypertension and cardiac failure. *Recurrent infections and respiratory failure are constant threats.

definition of bronchiectasis

Chronic necrotizing inflammation in bronchial wall leading to destruction of smooth muscle, elastic tissue, and cartilage and resulting in cylindrical or saccular permanent dilatation. It is not a primary disease but rather secondary to persisting infection or obstruction caused by a variety of conditions. Once developed, it gives rise to a characteristic symptom complex dominated by cough and expectoration of copious amounts of purulent sputum.

- Fluid, tumor, air in pleural cavity (tension pneumothorax)

Compression Atelectasis

Mediastinum shifts AWAY from the affected lung

Compression Atelectasis

Probably underlies many of the cases of spontaneous pneumothorax in young adults

Distal Acinar (Paraseptal) Emphysema

Someone has a tension pneumothorax, think about possibility of a_____ ruptureing

Distal Acinar (Paraseptal) Emphysema

The emphysema is more striking adjacent to the pleura, along the lobular connective tissue septa, and at the margins of the lobules.

Distal Acinar (Paraseptal) Emphysema

The proximal portion of the acinus is normal, the distal part is predominantly involved

Distal Acinar (Paraseptal) Emphysema

multiple, contiguous, enlarged air spaces ranging in diameter from less than 0.5 mm to more than 2.0 cm, some- times forming cystic structures that, with progressive enlargement, are referred to as bullae.

Distal Acinar (Paraseptal) Emphysema

occurs adjacent to areas of fibrosis, scar- ring, or atelectasis and is usually more severe in the upper half of the lungs.

Distal Acinar (Paraseptal) Emphysema

EMPHYSEMA

EMPHYSEMA

a chronic obstructive airway disease char- acterized by permanent enlargement of air spaces distal to terminal bronchioles.

Emphysema Smoking and inhaled pollutants cause ongoing accumula- tion of inflammatory cells, releasing elastases and oxidants, which destroy the alveolar walls without adequate mes- enchymal repair response.

Similarities between chronic bronchitis and emphysema

In severe or advanced cases of both, small airway disease (chronic bronchiolitis) is characteristic. Although chronic bronchitis may exist WITHOUT demonstrable emphysema, and PURE emphysema may occur (particularly in patients with inherited α1-antitrypsin deficiency) (discussed later), the two diseases usually COEXIST.

Patients who suffer a perforating injury (e.g., a fractured rib) are at risk for

Interstitial edema

Almost invariably associated with scarring, such as that resulting from healed inflammatory diseases.

Irregular emphysema

Although clinically asymptomatic, this may be the most common form of emphysema.

Irregular emphysema

¥ Acinus is irregularly involved ¥ Almost invariably associated with scarring ¥ May be the most common form of emphysema; careful search of most lungs at autopsy shows one or more scars from a healed inflammatory process ¥ Foci of irregular emphysema are usually asymptomatic and clinically insignificant

Irregular emphysema

- Primary ciliary dyskinesia - Sinus inversus - Bronchiectasis - Sinusitis - Infertility

Kartagener Syndrome

If a person has sinus inversus (heart on the right side) then you should suspect

Kartagener syndrome

CONTRACTION ATELECTASIS

Local or generalized fibrotic changes in the pleura or lung - prevent full expansion - Irreversible

Effects of CF

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a complex chloride channel and regulatory protein found in all exocrine tissues. Deranged transport of chloride and/or other CFTR-affected ions, such as sodium and bicarbonate, leads to thick, viscous secretions in the lungs, pancreas, liver, intestine, and reproductive tract, and to increased salt content in sweat gland secretions --> sterility in males --> pancreatic insufficiency --> thick, viscous secretions --> high salt in sweat --> bronchiectasis/lung disease

what kind of pneumonia may predispose affected patients to development of bronchiectasis.

Necrotizing, or suppurative, pneumonia, particularly with virulent organisms such as Staphylococcus aureus or Klebsiella spp.,

OBSTRUCTIVE LUNG (AIRWAY) DISEASES

OBSTRUCTIVE LUNG (AIRWAY) DISEASES

: Generalized, diffuse enlargement of all parts of the pulmonary acinus including respiratory bronchioli, alveolar ducts and alveoli

Panacinar emphysema

occurs in α1-antitrypsin deficiency.

Panacinar emphysema

tends to occur more commonly in the lower lung zones

Panacinar emphysema

the acini are uniformly enlarged, from the level of the respiratory bronchiole to the terminal blind alveoli

Panacinar emphysema (The "pan" refers to the entire acinus, not to the entire lung)

Definition of Chronic Bronchitis

Present in any patient, who has persistent cough with sputum production for at least 3 months in at least 2 consecutive years in the absence of any other identifiable disease

pink puffers

Pure emphysema patients

Reid index

Ratio of the thickness of the mucous gland layer to the thickness of the bronchial wall between the epithelium and the cartilage - Normal = 0.4

Mediastinum shifts TOWARD the atelectasis

Resorption Atelectasis

what does the liver look like in CF

Shrunken, cirrhotic/fibrotic, nodular liver

Liver in alpha-1 AT deficiency

The enzyme accumulates particularly in the periportal hepatocytes and can lead to lever damage and cirrhosis

Reversible atelectases

all except compression Resorption and Compression atelctasis are reversible Compression atelectasis is not

is CF autosomal dominant or recessive

autosomal recessive

cigarette smoking is common to

both chronic bronchitis and emphysema

Cor Pulmonale

bronchitis=common Emphysema= rare, terminal

Cystic Fibrosis

can be a cause of bronchiectasis

CF is most common amongst

caucasians

Present in any patient, who has persistent cough with sputum production for at least 3 months in at least 2 consecutive years in the absence of any other identifiable disease

chronic bronchitis

anatomic distribution of emphysema vs chronic bronchitis

chronic bronchitis initially involves the large airways, whereas emphysema affects the acinus.

Primary initiating factor for Chronic Bronchitis is

chronic irritation by inhaled substances: - tobacco smoke - dust (grain, cotton, silica, etc.) - environmental indoor and outdoor air pollution

Chronic bronchitis is common among

cigarette smokers and urban dwellers in smog-ridden cities

The diagnosis of chronic bronchitis is made on

clinical grounds: it is defined by the presence of a persistent productive cough for at least 3 consecutive months in at least 2 consecutive years.

α1 AT is encoded by

codominantly expressed genes in the polymorphic Pi locus on chromosome 14

Abnormal permanent enlargement of the air spaces distal to the terminal bronchioli accompanied by destruction of their walls

emphysema

tissue destruction withOUT fibrosis

emphysema

Obstructive diseases

emphysema, chronic bronchitis, asthma, and bronchiectasis

Diameter of peripheral bronchus is greater than that of its accompanying pulmonary artery.

in bronchiectasis

Artificially ventilated patients (esp premies) are at risk for

interstitial edema

The primarily_____ airflow obstruction of COPD distinguishes it from asthma, which, as described later, is characterized largely by reversible airflow obstruction; however, patients with COPD commonly have some degree of reversible obstruction as well

irreversible - COPD reversible - Asthma

PiZZ

is associated with markedly decreased serum levels of α1- AT

acinus

is the structure distal to terminal bronchioles, and a cluster of three to five acini is called a lobule

Bronchiectasis usually affects what parts of the lung

lower lobes bilaterally particularly those air passages that are most vertical When caused by tumors or aspiration of foreign bodies the involve- ment may be sharply localized to a single segment of the lungs. Usually, the most severe involvement is found in the more distal bronchi and bronchioles.

Chronic Bronchitis is most frequent in

middle-aged men, but both sexes are affected ¥ 90% of patients are smokers ¥ Most common in heavy smokers regardless of age, sex, occupation, and geography

The usual presenting symptoms and signs in CF include

persistent pulmonary infection, pancreatic insufficiency, and elevated sweat chloride levels.

Chronic obstructive component of chronic bronchitis largely results from

small airway disease (chronic bronchiolitis) and coexistent emphysema.

definition of emphysema vs chronic bronchitis

the definition of emphysema is morphologic = Abnormal permanent enlargement of the air spaces distal to the terminal bronchioli accompanied by destruction of their walls whereas chronic bronchitis is defined on the basis of clinical features = Present in any patient, who has persistent cough with sputum production for at least 3 months in at least 2 consecutive years in the absence of any other identifiable disease

In emphysema there is loss of not only epithelial and endothelial cells but also mesenchymal cells, leading to lack of extracellular matrix, the scaffolding upon which epithelial cells would have grown.

true

Senile emphysema

¥ Age-related loss of lung mass (atrophy) ¥ Affects the entire lung but is often more pronounced in the upper lobes

Interstitial emphysema

¥ Air in the connective tissue stroma of the lung, mediastinum, or subcutaneous tissue ¥ Causes: o Alveolar tears o Chest wounds that allows air to be sucked in o Fractured ribs that punctures the lung o Inhalation of irritant gases

Pathogenesis of emphysema

¥ Alveolar wall destruction results from protease - antiprotease imbalance and oxidant - antioxidant imbalance ¥ Exposure to toxic substances such as tobacco smoke and inhaled pollutants induces ongoing inflammation with accumulation of neutrophils, macrophages and CD8+ T lymphocytes in the lung. results in the release of leukotriene B4, IL-8, TNF and other mediators ¥ Elastases, cytokines (including IL-8) and oxidants are released causing epithelial injury and proteolysis of the extra- cellular matrix (ECM). ¥ Elastin degradation products further increase the inflammation ¥ Elastase, proteinase 3, and cathepsin from neutrophils and Matrix metalloproteinases from neutrophils and macrophages ¥ Any stimulus that increases neutrophils in the lung will increase elastolytic activity (tobacco) ¥ Air pollutants and tobacco smoke act by oxidizing alpha1-antitrypsin and other antiproteases ¥ Inherited α1-antitrypsin deficiency

Congenital Lobar Overinflation:

¥ Apparent at birth ¥ Probably results from HYPOPLASIA of bronchial cartilage ¥ Sometimes associated with other congenital cardiac and lung abnormalities

Histologic features of chronic bronchitis

¥ Chronic inflammation in the airways ¥ the mucosal lining of the larger airways usually is hyperemic and swollen by edema fluid. ¥ It is often is covered by a layer of mucinous or mucopurulent secretions. The smaller bronchi and bronchioles also may be filled with similar secretions. ¥ In trachea and larger bronchi: Hyperplasia of bronchial submucosal glands with increased proportion of mucous to serous cells ¥ Increased Reid index ¥ Reserve cell and goblet cell hyperplasia ¥ Squamous metaplasia common ¥ Acute exacerbations with bronchocentric pneumonia common ¥ Chronic bronchiolitis (small airway disease), characterized by goblet cell metaplasia, mucous plugging, inflammation, and fibrosis, is also present. ¥ In the most severe cases, there may be com- plete obliteration of the lumen as a consequence of fibrosis (bronchiolitis obliterans). ¥ It is the submucosal fibrosis that leads to luminal narrowing and airway obstruction ¥ Changes of emphysema often co-exist (chronic bronchitis with significant airflow obstruction is almost always complicated by emphysema).

Compensatory (Hyperinflation ) Emphysema:

¥ Dilation of alveoli but no destruction of septal walls in response to loss of lung substance elsewhere ¥ Results from hyperexpansion of the residual lung following surgical removal of a diseased lung or lobe

Morphology of emphysema

¥ Enlargement of air spaces ¥ Destruction of alveolar walls without fibrosis, leading to enlarged air spaces ¥ Destruction of alveolar walls, alveolar ducts and respiratory bronchioli ¥ "Free-floating" islands of tissue ¥ Bullae In addition to alveolar loss, the number of alveolar capillaries is diminished. Terminal and respiratory bronchioles may be deformed because of the loss of septa that help tether these structures in the parenchyma. With the loss of elastic tissue in the surrounding alveolar septa, radial traction on the small airways is reduced. As a result, they tend to collapse during expiration—an important cause of chronic airflow obstruction in severe emphysema. Bronchiolar inflammation and submucosal fibrosis are consistently present in advanced disease.

Infection and chronic bronchitis

¥ Infection is a secondary, but significant factor: - maintains inflammation - produces acute exacerbations

Obstructive Overinflation:

¥ Lung expands because air is trapped within it ¥ Causes: *Subtotal obstruction by a tumor or foreign object* ¥ Mechanisms: - *Ball-valve action of the obstructive agent; air enters on inspiration but cannot leave on expiration* - *Ventilation through collaterals may bring in air from behind the obstruction (pores of Kohn and canals of Lambert)* ¥ Can be a life-threatening emergency, if the affected portion distends sufficiently to compress the remaining normal lung

the 3 common etiologies of emphysema

¥ Smoking ¥ Air pollution ¥ Alpha-1-antitrypsin deficiency

Bullous emphysema

¥ large *SUBPLEURAL* blebs or bullae (>1 cm in diameter in the distended state) ¥ Can occur in ANY form of emphysema ¥ Represents localized accentuations of emphysema ¥ Occurs near the APEX, sometimes in relation to old SCARS ¥ Rupture of the bullae may give rise to PNEUMOTHORAX

in emphysema, alveolar destruction results from

¥ protease - antiprotease imbalance and oxidant - antioxidant imbalance The protease-antiprotease imbalance and oxidant-antioxidant imbalance are additive in their effects and contribute to tissue damage. α1-antitrypsin (α1-AT) deficiency can be either congenital or "functional" as a result of oxidative inactivation.