The Lung Flashcards
respiratory system embryology
Outgrowth from the ventral wall of the foregut
Lobar bronchi lined with what and do what
Columnar calibrated epithelium with abundant subepithelial glands that produce mucus, which impedes the entry of microbes
Tell my about the lungs double arterial supply
Pulmonary arteries from the heart carry de oxygenated blood to the alveoli
Bronchial arteries from the aorta carry oxygenated blood to the parenchyma
Lining of the respiratory tract
Pseudostratified ciliated columnar epithelium with goblet cells
Neuroendocrine cells are present that release several factors
-serotonin 5HT, calcitonin, gastrin releasing peptide (bombesin)
Mucus secreting goblet cells and submucosal glands are dispersed through the walls of the trachea and bronchi, but not the bronchioles and distal
Exception: what are the vocal cords lined by
Stratified squamous epithelium
Alveolar epithelium
Continuous layer of two cell types
Alveolar epithelium type I
95%
Flattened and plate like
Rounded type II pneumocytes alveolar epithelium
Synthesize surfactant
Repair alveolar epithelium by giving rise to type I—stem cel like
Pulmonary hypoplasia
Defective lung development due to abnormalities that compress the lung or impede normal expansion in utero (diaphragmatic hernia or oligohydramnios)
Diminished weight, volume, and acinar number for body weight and gestational age
If severe, can be fatal in the early neonatal period
Foregut cysts
Due to abnormal detachment of primitive foregut
Most often in hilum or middle mediastinum
Bronchogenic (most common), esophageal, or enteric—depending ont he wall structure
Bronchogenic cysts
Most commmon and is rarely connected to the tracheobronchial tree
Lined with ciliated pseudostratified columnar epithelium with glands, cartilage and smooth muscle in the wall
Usually found incidentally of there is compression of nearby structures
Pulmonary sequesteration lung tissue
Lacks any connection to the airway system
Has abnormal vascular supply arising from the aorta or its branches
Extra lobar sequesteration
Lack connection to the airway system and are external to the lung
Has own pleura
Generally come to attention as mass lesions in infants
Often associated with other congenital anomalies
Intra lobar sequesteration
Occur within the lung parenchyma
Does not have its own pleura
Lack connection to the airway system
Occur in older children due to recurrent localized infection or bronchiectasis
Neonatal RDS
Most common where a layer of hyaline proteinaceous material int he peripheral airspace’s of infants who have the condition
Other causes of neonatal respiratory distress syndrome
Excessive sedation of mom, fetal head delivery during birth, aspiration of blood or amniotic fluid, or intrauterine hypoxia fromthe umbilical cord around the neck
How does neonatal respiratory distress present
Preterm with appropriate weight, may need assistance breathing during the first few minutes, then normal, then problems in 30 min, cyanosis in a few hours
Lungs RSD
Fine rales in lung fields
CXR RSD
Uniform minute reticulogranular densities that look like ground glass
Prognosis neonatal RSD
Infant will typically be able to survive if the therapy is able to keep them alive for the first few days
Who gets neonatal RSD
Males, maternal diabetes, delivery by C section
Pathogensisof RDS
Immaturity of th lungs is the most important thing for RDS to develop
Happens to 60% of infants bone less than 28 weeks
Fundamental problem is a lack of surfactant and thus too much surface tension int he alveoli
Surfactant composition
Defense proteins: SP-A and SP-D
Surfactant proteins : SP-B, SP-C and surfactant lipids
-can measure these in an amniocentesis
Surfactant genes
SFTPB, SFTBC
Surfactant defiency issue
Infants need the surfactant to properly inhale with less effort, but if they don’t have any then each progressive breath the lungs collapse a little more
This problem of stiff atelectatic lungs is compounded by a soft thoracic wallet hat is pulled in as the diaphragm descends
Progressive atelectasis and reduced lung compliance->
Protein rich, fibrin rich exudation into the alveolar spaces with the formation of hyaline membranes
- fibrin hyaline membranes are barriers to gas exchange->CO2 retention and hypoxemia
- hypoxemia impairs further surfactant synthesis
Hypoventilation !!!
What does hypoventilation from RSD lead to
Acidosis and pulmonary vasoconstriction (from the relative hypoxia) leading to pulmonary hypoperfusion causing tissue damage and plasma leak into the alveoli
Ultimately there are necrotic cells and fibrin deposition with a hyaline membrane being laid down and exacerbating the problem in a viscous cycle
Surfactant synthesis
Produced by type II pneumocytes
Modulated by cortisol (glucocorticoids most important*), prolactin, thyroxine, and TGFB
Conditions associated with what increase ___ release and lower the risk of developing RDS
Intrauterine stress and FGR
Corticosteroid
Diabetic mom
Increased glucose in mother leads to increased insulin in fetuses. Increased insulin in fetus inhibits synthesis of surfactant by way of inhibiting the steroids leading to a greater risk of RDS
- infants of diabetic mom have higher risk of developing RDS
- treat with corticosteroid therapy
How treat infant of diabetic mother
Corticosteroid therapy
Labor and surfactant
Labor increases surfactant synthesis
C section before onset of labor
Increases risk of RDS
C section is less stressful for baby and labor increases surfactant
Morphology RDS
Lungs are normal size, solid airless, and reddish purple in color
Alveoli are poorly developed and collapsed—atelectasis
Necrotic cells (including type II pneumocytes) can be seen early and later they are incorporated within eosinophilic hyaline membranes that are also composed of fibrin
NEVER seen in stillborn
Infants that survive more than 48 hours will have reparative changes int he lungs where the alveolar epithelium proliferated under the surface of the membrane and detach into the airspace where is digested by macrophages
Clinical features of RDS
Clinical course and prognosis depends on the maturity and birth weight of the infant and the promptness of institution of therapy (administration of surfactant: poractant Alfa, bear tang, calfactant)
Best thing to do is delay labor long enough to reach maturity or induce maturation of the lungs
Best way to check on lung maturity
Sample the phospholipids in the amniotic fluid
- phosphatidylcholine is important for surfactant
- measure a lecithin: phosphatidylcholine ratio; want it to be greater than 2:1?
In uncomplicated cases of RDS when get recovery
3-4 days
Complications from high concentration of ventilator administered oxygen for prolonged periods for infants with RDS
Retrolental fibroplasia
Bronchopulmonary dysplasia
Retrolental fibrosis(retinopathy of prematurity)
Phase I: hyperoxaluria; expression of VEGF is decreased and causing endothelial cell apoptosis
Phase II:VEGF levels rebound after return to relatively hypoxic room air
-induced retinal vessel proliferation (neovascularization) that is characteristic of the retina lesions
Bronchopulmonary dysplasia
Major abnormality: striking decrease in alveolar septation (manifested as large, simplified alveolar structures) and a dysmorphic capillary configuration
caused by a potentially reversible impairment in the development of alveolar septation at the “saccular stage”
Multiple factors: hyperoxemia, hyperventilation, prematurity, inflammatory cytokines (TNF, IL-1, IL-6, and IL-8), and vascular maldevelopment
Infants who recover from RDS are at an increased risk of
PDA, intraventricular hemorrhage, necrotizing enterocolitis
Atelectasis (collapse)
Incomplete expansion of the lungs (neonatal atelectasis) or collapse of previously inflated lung producing areas of relatively airless pulmonary parenchyma
Can reduce oxygenation and predispose to infection
Reversible (except in contraction)
Resorption atelectasis=obstruction
Complete airway obstruction
air is resorbed from the dependent alveoli which then collapse
Mediastinum shifts towards the affected lung because lung volume is diminished
most often caused by excessive secretions (mucus plug) or exudates within smaller bronchi as may occur in bronchial asthma, chronic bronchitis, bronchiectasis, or post-operative setting
Can also be due to aspiration or tumor fragments
Compressive atelectasis=pleural effusion
occur whenever significant volumes of fluid accumulate within the pleural cavity
Transudate (hydrothorax), exudate (pleural effusion), blood (hemothorax), air (pneumothorax), tumor
Effusion from cardiac failure/neoplasm
Blood from aneurysm rupture
Mediastinum shifts away from the affected lung
Contraction atelectasis =fibrosis
focal or generalized pulmonary or pleural fibrosis prevent full expansion
Mediastinum can shift toward the affected lung if it is ipsilateral, no change if it is bilateral
Irreversible
Pulmonary edema
leakage of excessive interstitial fluid in alveolar spaces due to:
Increased hydrostatic pressure
Increased capillary permeability
Leads to heavy, wet lungs regardless of etiology
Decreased oxygenation – diffusion barrier is increased –> cyanosis, dyspnea, low O2 sat
Predisposes patient to infection
Therapy and outcome depend on the etiology
Hemodynamic pulmonary edema
Engorged alveolar capillaries
due to increased hydrostatic pressure, often a result of left-sided heart failure
Fluid accumulation occurs in basal regions of lower lungs first (dependent edema)
Granular, pink precipitates in the alveolar spaces
Chronically leads to brown, firm lungs (brown induration) due to interstitial fibrosis and hemosiderin laden macrophages (pathognomonic “heart failure cells”)
Edema caused by microvascular (alveolar injury
due to injury of the alveolar septa
inflammatory exudate that leaks into the interstitial space and, in more severe cases, the alveoli
in most forms of pneumonia, the edema remains localized and is overshadowed by the manifestations of infection
If diffuse/severe can lead to Acute Respiratory Distress Syndrome (ARDS)
Acute lung injury and acute respiratory distress syndrome (diffuse alveolar damage)
Ok
Noncardiogenic pulmonary edema (acute lung injury ALI)
Abrupt onset of hypoxemia and bilateral pulmonary infiltrates in the absence of heart failure
Increased pulmonary vascular permeability due to epithelial cell death
ARDS is a manifestation of severe ALI/DAD
ARDS and ALI are associated with inflammation-associated increases in pulmonary vascular permeability, edema, and epithelial cell death
histologically, this is recognized as diffuse alveolar damage (DAD)
due to localized or systemic insult
Sepsis, diffuse pulmonary edema, gastric aspiration, and trauma account for more than 50% of the cases
Worse prognosis in smokers and alcoholics
pathogenesis is a “viscous cycle of increasing inflammation and pulmonary damage
ARDS is a manifestation of
Severe ALI/DAD
ALI/ARDS: endothelial activation
There is injury to pneumocyte injury that is recognized by resident macrophages (“dust cells”)
Can also be activated by systemic factors in times of sepsis
Then there is increased endothelial permeability and adhesion molecules
There are also increased production and secretion of procoagulant proteins and chemokines
ALI/ARDS: adhesion and extravasion of neutrophils
neutrophils come in and degranulate –> release inflammatory mediators including proteases, reactive oxygen species, and cytokines
macrophage inhibitory factor (MIF) helps to sustain the pro-inflammatory response
result: increased recruitment and adhesion of leukocytes –> more endothelial injury –> local thrombosis
this cycle of inflammation and endothelial damage lies at the heart of ALI/ARDS
ALI/ARDS: accumulation if intraalveolar fluid and formation of hyaline membranes
The alveolar caps become leaky and allow the edema to come in
Type II pneumocytes are damaged which results in surfactant-related issues (i.e. gas exchange becomes worse –> shortness of breath)
The protein-rich fluid and dead epithelial cells then forms in hyaline membranes (characteristic of ALI/ARDS
ALI?ARDS: resolution of injury
Impeded due to epithelial necrosis and inflammatory damage that impairs edema resorption
Eventually, if the inflammation lessens then the macrophages can clean everything up and heal the damaged areas with fibrogenic factors (i.e. TGF-β and PDGF)
There is then fibrosis of the alveolar walls and bronchiolar stem cell replacement of pneumocytes
Type II Pneumocytes replace the pneumocytes, act as stem cells
ALI?ARDS: acute morphology
Lungs are diffusely firm, red, boggy and heavy (hyperemic and congested?)
Congestion with interstitial and intraalveolar edema, inflammation, fibrin deposition, and diffuse alveolar damage
Lined with hyaline membranes (composed of necrotic epithelial debris and exuded proteins)
morphologically similar to those seen in hyaline membrane diseases of neonates
alveolar hyaline membranes consist of fibrin-rich edema fluid mixed with the cytoplasmic and lipid remnants of necrotic epithelial cells (protein-rich exudate)
Characteristic histologic picture of ARDS is that of hyaline membranes lining alveolar walls. Edema, scattered neutrophils and macrophages, and epithelial necrosis are also present
ALI/ARDS: organizing stage morphology
Type II pneumocyte proliferation
Granulation tissue forms in the alveolar walls as a response to the hyaline membranes
most cases: granulation tissue resolves and leaves only minimal functional impairment
can progress to interstitial fibrosis with severe scarring
Superimposed bronchopneumonia can be fatal
ALI/ARDS: clinical
LI/ARDS: Clinical
ALI or ARDS patients are usually already admitted for one of the predisposing conditions (e.g. sepsis, severe head trauma)
Dyspnea and tachypnea are characteristic –> cyanosis, hypoxemia, respiratory failure, and the appearance of diffuse bilateral infiltrates follow
hypoxemia may be refractory to oxygen therapy due to ventilation/perfusion mismatching
Respiratory acidosis can develop (can’t blow off CO2 as effectively –> buildup of CO2 –> acidosis)
Stiff lungs from the lack of surfactant can develop early in the course
Functional abnormalities are not evenly distributed
Poorly aerated regions are still perfused = V/Q mismatch & hypoxemia
Ventilation is occurring, but there in not as much perfusion as expected
Mortality ALI/ARDS
40% secondary to sepsis of multi organ failrue
ALI/ARDS:treatment
Mechanical ventilation while treating the underlying cause
no proven specific treatments – treatment of the underlying cause has improved
Most patients will recover, but many of them can still have physical and cognitive impairment
most deaths are attributable to sepsis or multiorgan failure and, in some cases, direct lung injury
In minority of cases, exudate and diffuse tissue destruction –> scarring, interstitial fibrosis, and chronic pulmonary disease
Acute interstitial pneumonia (idiopathic (ALI/DAD)
Widespread ALI of unknown etiology with a rapidly progressive clinical course
Present with acute respiratory failure within 3 weeks of URI
Imaging/pathology identical to organizing ALI
Average age: 59; No gender preference
33-74% mortality, typically in first 12 months
Morphology is the same as the organizing stage of ALI
Progresses rapidly with most deaths occurring in 1-2 months
Survivors are prone to recurrence and chronic interstitial disease
Obstructive and restrictivelung diseases
Increased resistance to airflow due to partial or complete obstruction at any level
Decreased maximal flow rates during forced expiration
FEV1 / FVC < 0.8
Restrictive lung disease
Decreased expansion of the lung parenchyma and decreased total lung capacity
Chest wall disorders (e.g. severe obesity, pleural diseases, kyphoscoliosis, and poliomyelitis)
Chronic interstitial and infiltrative disease (e.g. pneumoconioses and interstitial fibrosis)
Proportionate Decreased in lung capacity and FEV1 –> FEV1 / FVC is normal
Chest wall disorders
Severe obesity, pleural diseases, kyphoscoliosis, and poliomyelitis
Chronic interstitial and infiltrating disease
Pneumoconiosis and infiltrative disease
Obstructive lung disease FEV1/FVC
Restrictive lung disease FEV1/FVC
Normal
Obstructive lung disease examples
COPD(emphysema, chronic bronchitis)
Asthma
Bronchiectasis
Chronic bronchitis
Anatomical site-bronchus
Major pathological changes-mucous gland hyperplasia, hypersecretion
Etiology:tobacco smoke, air pollutants
Signs and symptoms :fought sputum production
Bronchiectasis
An atomic site: bronchi
Major pathology changes: airway dilation and scarring
Etiology: persistent or severe necrotizing infections
Signs and symptoms: cough, pursuant sputum, fever
Asthma
Anatomic site: bronchus
Major pathological changes: smooth msucle hyperplasia, excess mucus, inflammation
Etiology: immunologic or unknown; drug induced
Signs and symptoms: episodic wheezing, cough, dyspnea
Emphysema
Anatomic site: acinus
Major pathological changes: airspace enlargement, wall destruction->blebs
Etiology: tobacco smoke: highly
Signs and symptoms: dyspnea
Small airway disease(variant of chronic bronchiolitis)
Can be seen with any form of obstructive disease or as an isolated finding: contributes to obstruction both in emphysema and chronic bronchitis
Reversible bronchitis
Asthma == reversible bronchospasm
chronic bronchitis and emphysema == irreversible bronchospasm
*Generally
COPD
C ommonly includes emphysema and chronic bronchitis
Increased risk: Cigarette smoking, female, African American, environmental/occupational pollutants, airway hyperresponsiveness, genetic polymorphisms
Emphysema
I rreversible enlargement of airspaces distal to the terminal bronchioles
Alveolar wall destruction without obvious fibrosis, except in the small airways
Classified by anatomic distribution within the lobule – centriacinar, panacinar, paraseptal, and irregular
lobule == cluster of acini (terminal respiratory units)
*only the first two cause clinically significant airflow obstruction
Centriacinar (centrilobular emphysema)
Destruction and enlargement of the central or proximal parts of the acini, formed by respiratory bronchioles, sparing distal alveoli
Emphysematous and normal airspaces exist within the same acinus and lobule
Predominantly upper lobes and apices
When severe, the distal acini may be involved (difficult to distinguish against panacinar emphysema)
Heavy smokers and often associated with chronic bronchitis (COPD)
Most common form of emphysema 95% of cases
Where is centriacinar emphysema, who gets it
Upper lobes and spices
Smokers
Most common form of emphysema
Centriacinar emphysema
Panacinar (panlobular) emphysema
Uniform destruction and enlargement of the entire acini from the level of the respiratory bronchiole to the terminal blind alveoli
Common in the lower zones and anterior margins of the lung
Most severe at the lung bases
Associated with α1-antitrypsin deficiency
Distal acinar emphysema
Proximal acinus is normal; distal acinus is predominantly affected
Prominent near the pleura, along septa and lobules and occurs adjacent to fibrosis/scarring/atelectasis
More severe in the upper half of the lungs
Multiple, continuous, enlarged airspaces that may sometimes form cyst-like structures – “blebs”
Commonly the underlying lesion in spontaneous pneumothorax in the young
Airspace enlargement with fibrosis (irregular emphysema)
Acinus is irregularly involved
Invariable associated with scaring
Clinically insignificant
Pathogenesis of emphysema
parenchymal destruction == emphysema
airway disease == bronchiolitis and chronic bronchitis
Emphysema pathogenesis L inflammatory mediators
Increased levels in the affected areas – leukotriene B4, IL-8, TBF, and others
Released by resident epithelial cells and macrophages
Attract inflammatory cells from circulation (chemotaxis)
Amplify inflammation (cytokines)
Induce structural changes (GFs)
Emphysema pathogenesis : protease antiprotease balance
connective tissue is broken down by enzymes released from the inflammatory and epithelial cells
Loss of elastic tissue = respiratory bronchiole collapse during expiration causing functional obstruction
Deficiency of antiproteases (may be genetic) is common in patients with emphysema
α1-antitrypsin == anti-protease; deficiency upsets the balance –> panlobular emphysema
trypsin is a protease; anti-trypsin is an anti-protease – don’t get fucked up on words
Emphysema pathogenesis: oxidative stress
Oxidants are produced by tobacco smoke, from alveolar damage, and from inflammatory cells
NFR2 inactivation: significantly increased sensitivity to tobacco smoke
NFR2 is a sensor for oxidants in alveolar epithelial cells
Activated by intracellular oxidants to upregulate genes that protect from oxidant damage
NFR2 == transcription factor that upregulates expression of multiple genes that protect cells from oxidant damage
Emphysema pathogenesis : infection
Thought to exacerbate the associated inflammation and chronic bronchitis
A1 antitrypsin (anti-protease) and emphysema
Found in 1% of all patients
anti-protease: protects against proteases, especially elastase (released by neutrophils)
Much more likely to cause emphysema, especially if the patient smokes
Encoded on the Pi locus of chromosome 14
patients with the Z allele have decreased serum levels and 80% of homozygotes (piZZ) will develop symptomatic panacinar emphysema which is even more accelerated and severe if the patient smokes
Nicotinic acetylcholine receptor and emphysema
Some genetic variants of the receptor can lead to an increased risk for the disease
Makes smoking more addictive and thus increases the risk of the disease
smoke more and smoking is even worse for you
Physiology emphysema
small airways are normally held open by the elastic recoil of the lung parenchyma
loss of elastic tissue in the walls of alveoli that surround respiratory bronchioles reduces radial traction and thus causes the respiratory bronchioles to collapse during expiration –> functional airflow obstruction
Smoking and airway changes, found even in young smokers
goblet cell hyperplasia and mucus plugging of the lumen
inflammatory infiltrates in bronchial walls – neutrophils, macrophages, B-cells, and T-cells
bronchiolar wall thickening due to fibrosis and smooth muscle hypertrophy –> increased airway obstruction
Emphysema morphology
Diffuse disease: voluminous lungs that overlap the heart
Alveolar wall rupture can produce huge airspaces (blebs and bullae) that are more commonly found in the upper 2/3 of the lungs that compresses the bronchioles and vasculature
Alveolar spaces are enlarged and separated by thin septa with only focal centriacinar fibrosis
The Pores of Kohn are large and look to be clubbed shape and protrude blindly into the alveolar spaces
Septal capillaries are compressed and bloodless
CLINCIALLY emphysema
Dyspnea, wheezing, cough begin to occur when 1/3 of pulmonary parenchyma is lost
Cough and expectorant are very variable and depend on the level of the associated bronchitis
Severe weight loss (confused with occult cancer)
Barrel chested, dyspneic, hunched over, breathes through pursed lips
impaired expiratory airflow (best measured through spirometry) is the key to diagnosis
‘Pink puffers’ well oxygenated at rest due to overventilation
chronic bronchitis == blue bloaters
emphysema == pink puffers
Prognosis emphysema
Development of cor pulmonale is a poor prognostic factor
Death due to:
Coronary Artery Disease
Respiratory Failure
Right Heart Failure
Massive collapse of lungs 2° to pneumothorax
Treat emphysema
Smoking cessation
O2 therapy
Long acting bronchodilators (tiotropiums and ipratropium) with inhaled corticosteroids
physical therapy
Bullectomy
Lung volume reduction surgery (select patients)
Lung transplant (select patients)
α1-antitrypsin replacement therapy is currently being evaluated
Other forms of emphysema
Associated with lung overinflation or focal emphysematous change
Compensatory hyperinflation emphysema
Dilation of alveoli in response to loss of lung parenchyma elsewhere
hyper-expansion of residual lung parenchyma following surgical removal of diseased lung or lobe
Obstructive overinflation emphysema
Foreign body (tumor, foreign object) creates a subtotal obstruction – the lung expands because air is trapped
Congenital Lobar Overinflation in infants due to hypoplasia of bronchial cartilage
sometimes associated with other congenital cardiac and lung abnormalities
Overinflation in Obstructive Lesions
Ball-valve phenomenon which admits air on inspiration but traps it on expiration
Collaterals introduce air behind the obstruction
pores of Kohn
canals of Lambert (bronchioalveolar connections)
Can be life-threatening as the affected lung can compress the remaining lung
Bulbous emphysema
Large sub-pleural bullae or blebs that can occur with any type of emphysema
Bullae: spaces of air that are greater than 1cm
Occurs near the apex
Often near old tuberculous scarring
Rupture can cause pneumothorax
Interstitial emphysema
Entry of air into connective tissue of the lung, mediastinum, or subcutaneous tissue
In most cases is due to alveolar tears in pulmonary emphysema allowing air to enter the stroma of the lungs, but can also be due to chest wound or fractured rib
rapid increases in pressure within the alveolar sacs (e.g. coughing with bronchiolar obstruction)
premature infants on positive pressure ventilation are most at risk
Artificially ventilated adults
Chronic bronchitis
Persistent cough with sputum production for at least three months in at least two consecutive years in the absence of other identifiable causes
Can accelerate decline in lung function, cause cor pulmonale and HF or atypical metaplasia of respiratory epithelium (fertile grounds for cancerous transformation)
Common in smokers and smog-laden cities
COPD spectrum == emphysema to chronic bronchitis
most patients have features of both
associate Reid Index with Chronic Bronchitis
Pathogenesis chronic bronchitis
Predominantly due to chronic irritation from inhaled substances/irritants such as tobacco smoke (90% of patients also smoke) and also dust from grain, silica, or cotton
earliest feature == hypersecretion of mucus in the large airways
associated with hypertrophy of the submucosal glands in the trachea and bronchi
With time there is increased numbers of goblet cells in the smaller airways too
Chronic inflammation leads to fibrosis and obstruction of the small airways
Exacerbated by 2° infections
Smoking inhibits cilia to prevent the clearing of mucous and thus increased risk of infection
Morphology chronic bronchitis
Hyperemia (excessive blood vessels)
Edema of lung mucous membranes
mild chronic inflammation of the airways (predominantly lymphocytes) and enlargement of the mucus-secreting glands of the trachea and bronchi – characteristic features of chronic bronchitis
Mucinous secretions filling airways
Mucous gland hyperplasia
hyperplasia == increase in size
Reid Index == ratio of the thickness of the mucous gland layer to the thickness of the wall between the epithelium and the cartilage
Normally is .4 or 40%; increased in chronic bronchitis in proportion to the severity and duration
associate Reid Index with chronic bronchitis – just the glandular component
don’t use the Reid Index for asthma
Bronchiolar inflammation, fibrosis, and gland hyperplasia leads to airway obstruction
Bronchial epithelium may exhibit squamous metaplasia + dysplasia
There is marked narrowing of bronchioles caused by mucus plugging, inflammation, and fibrosis
Severe: bronchiolitis obliterans (fibrosis causes obliteration of the lumen in severe cases
Clinical chronic bronchitis
y
Persistent cough productive of sparse sputum for at least three consecutive months in at least two consecutive years
eventually, dyspnea on exertion develops
hypercapnia (retain CO2), hypoxemia and mild cyanosis over time – “blue bloaters”
chronic bronchitis == blue bloaters
emphysema == pink puffers
Can lead to cor pulmonale and heart failure
Death is possible from further impairment of respiratory function due to superimposed acute infections
Asthma
disorder of the conducting airways
episodic reversible bronchospasm due to smooth muscle hyperreactivity, inflammation of the bronchial walls, and increased mucus production
Leads to cough, wheeze, chest tightness, and breathlessness, especially at night and in the morning
Classes of asthma
Atopic (most common0
Nonatopic
Atopic asthma
Classic IgE-mediated (Type I) hypersensitivity reaction triggered by environmental allergens (e.g. pollen, food) that is synergistically triggered by other proinflammatory things in the environment and viral infections
Early onset allergic asthma
Associated with TH2 helper T cell mediated inflammation and responds well to treatment with corticosteroids
Genetic atopic asthma
Family history common
Skin test atopic asthma
Immediate wheal and far reaction to the antigen they are sensitized to
Serum test atopic asthma
Levels of allergen sensitization shown by RAST which can detect the presence of IgE antibodies that are specific for individual allergens
Nonatopic asthma
No evidence of allergen sensitization
Negative skin test
Genetic involvement less common
viral respiratory infections are common triggers, as well as inhaled air pollutants (smoking, sulfur dioxide, ozone, and nitrogen dioxide == smog) that can cause chronic airway inflammation and hyperreactivity
ozone has no pathologic effects; it is only an irritant
Can even be caused by cold or exercise
Drug induced asthma (triad asthma)
Aspirin sensitive asthma == uncommon; occurs in individuals with recurrent rhinitis and nasal polyps
exquisitely sensitive to small doses of aspirin and other NSAIDs
asthmatic attacks + urticaria (hives)
Inhibition of COX pathway –> decreased PGE2 –> increase in pro-inflammatory leukotrienes
NSAIDs
More likely to occur in individuals with recurrent rhinitis and nasal polyps
Occupational asthma
Minute quantities of chemicals induces signs and symptoms after repeated exposure
Varying underlying mechanisms
Asthmatic bronchitis
Seen in smokers
Early phase atopic asthma
TH2 hyperreactivity leads to:
IL-4: production of IgE – “5Always and 4Ever”
IL-5: activates eosinophils
IL-13: stimulates bronchial submucosal glands to secrete mucous and B-cells to make more IgE
Antigen binding to IgE coated mast cells causes primary and secondary mediator release that cause:
T-lymphocytes and epithelial cells secrete chemokines that recruit more T-lymphocytes and eosinophils and exacerbate the problem
Early phase atopic asthma
Bronchoconstriction triggered by direct stimulation of subepithelial vagal (parasympathetic) receptors through both central and local reflexes
increased mucus production
variable degrees of vasodilation
increased vascular permeability
Late phase atopic asthma (hours
dominated by the recruitment of leukocytes, notably eosinophils, neutrophils, and more T-cells
Persistent bronchospasm and edema
Leukocytic infiltration
Epithelial damage and loss
Repeated bouts lead to airway remodeling – asthma == airway remodeling
Hypertrophy and hyperplasia of bronchial smooth muscle and mucus glands
Increased vascularity
Increased deposition of subepithelial collagen
TH2 is the dominant cell type
TH17 T-cells are also present and they are the ones that recruit neutrophils
down regulation of IL-17 == cold abscesses
Mediators whose role in asthmatic bronchospasm is clearly supported by. Pharmacological intervention
Leukotrienes C4, D4, E4
Acetylcholine
Leukotrients C4, D4, E4
Prolonged bronchoconstriction, vascular permeability, and mucus secretion
Acetylcholine
Stimulation of muscarinic receptors causing airway smooth muscle constriction
Mediators found in asthmatic bronchospasm, but not significant targets of pharmaceutical intervention
Histamine PGD2 PAF Cytokines and chemokines ^might prove important in certain types of chronic or non allergic asthma
Histamine:
Bronchoconstrictor
PGD2
Bronchoconstriction and vasodilation
Asthma genetics
Patients with atopic asthma are more likely to have other allergic disorders like allergic rhinitis and eczema
Implicated genes can affect 1° or 2° immune responses, tissue remodeling or the patients response to therapy
Gene cluster involving IL3, IL4 IL5 IL9 IL13 and IL4R, on chromosome 5q
Polymorphism in the IL13 gene have the strongest and most consistent association with asthma
Genetics asthma
IL4R HLA class II
ADAM33 leads to bronchial smooth muscle and fibroblast proliferation
B2-adrenergic receptor (airway reactivity)
YKL-40: increased levels of the China tase-like glycoproteins is directly correlated with disease severity , airway remodeling, and decreased pulmonary function
Environmental factors
City Living – there are many airborne pollutants that may initiate the TH2 response; city life limits the exposure of very young children to certain antigens
infections themselves are not a cause of asthma
young children with aeroallergen sensitization who develop lower respiratory tract viral infections (rhinovirus type C, respiratory syncytial virus) have 10-30x increased risk of developing persistent and/or severe asthma
viral and bacterial infections are associated with acute exacerbations of the disease
airway remodeling = structural changes in the bronchial wall brought on as a result of repeated bouts of allergen exposure and immune reactions; irreversible component
hypertrophy and hyperplasia of bronchial smooth muscle
epithelial injury
increased airway vascularity
increased subepithelial mucus gland hypertrophy
deposition of subepithelial collagen
Asthma morphology
The following is especially found in patients with status asthmaticus
Overinflated lungs with patchy atelectasis
Mucus plugging of airways that also contains shed epithelium
Whorled mucus plugs (Curschmann spirals)
Microscopic lung edema, with eosinophils and Charcot-Leyden crystals (eosinophilic protein galectin-10)
Airway remodeling == irreversible component; this is seen in asthma
Thickening of airway wall
Subbasement membrane fibrosis (deposited I and III collagen)
Increased vascularity
Bronchial wall smooth muscle and mucosal gland hypertrophy
Clinical course asthma
Attacks can be hours long Chest tightness Prolonged expiration Peripheral blood eosinophilia Wheezing Dyspnea Cough **atopic dermatitis**: rash on flexural surfaces asthma == eosinophils, IL-5, Curschmann spirals, Charcot-Leyden crystals
Status asthmaticus
Severe form of asthma where the paroxysm persists for days and weeks
Airflow obstruction may be so severe it causes cyanosis or death
Asthma and puberty
About half of the cases will remit, but lots of cases will return in adulthood
Bronchiectasis
Destruction of smooth muscle and elastic tissue by chronic necrotizing infections that leads to permanent dilation of bronchi and bronchioles
becoming less common due to infection control
Etiology bronchiectasis
Congenital or hereditary conditions like cystic fibrosis and primary ciliary dyskinesia
Infection(s), including *necrotizing pneumonia caused by bacteria, viruses, and fungi
Bronchial obstruction, due to tumor, foreign body, or mucus impaction
bronchiectasis is localized to the obstructed lung segment
Chronic inflammatory states: RA, lupus, IBD, COPD, post-lung/bone marrow transplant
25-50% of cases are idiopathic
Pathogenesis bronchiectasis
Obstruction and infection are both necessary but can occur in either order
Bronchial obstruction impairs normal clearing mechanisms
secretions pool distal to the obstruction and can lead to secondary infection and inflammation
Severe infections can lead to inflammation accompanied by necrosis, fibrosis, and eventually airway dilation
The smaller airways can become obliterated: bronchiolitis obliterans
Cystic fibrosis
Abnormal function or loss of an epithelial chloride channel (CFTR) on chromosome 7
CFTR transports Cl
Sweat glands: from the surface into the cell
Other epithelia: from the cell to the lumen
CFTR ENaC
CFTR inhibits ENaC which is found on epithelial cell apical surfaces (except on sweat glands) and thus in CF it is overactive taking up water and Na+ ions from the mucus in the lungs
What does dehydration of the airway mucus lead to in CF
T he dehydration of the airway mucus leads to decreased ciliary activity and an inability for the body to clear mucous and microbes –> airway obstruction, predispose to (necrotizing) infection –> bronchiectasis
primary defect in ion transport –> defective mucociliary action and airway obstruction by thick secretions
chronic bacterial infections are common –> widespread damage to airway walls
Bacterial pathogenesis CF
Staphylococcus aureus, haemophilus influenzae, and burkholderia capacia
Pseudomonas aeruginosa CF
Can produce a mucosa capsule (alginate)->protective biofilm
Primary ciliary dyskinesia
Autosomal recessive
Defect in ciliary motor proteins (dynein) –> retention of secretions –> recurrent infection –> bronchiectasis
Half of patients also have Kartagener Syndrome: situs inversus or partial lateralizing abnormality, bronchiectasis, and sinusitis
Males usually infertile due to sperm dysmotility
Allergic bronchopulmonary asperigillosis
Occurs in patients with asthma and cystic fibrosis who develop periods of exacerbation and remission which can lead to proximal bronchiectasis and fibrotic lung disease
Hypersensitivity to the fungus aspergillus fumigatus
Activation of TH2 helper T cells that recruit eosinophils and other leukocytes
Elevated IgE serum antibodies to the fungus
Characterized by formation of mucous plugs and intense airway inflammation with eosinophils
Bronchiectasis morphology
Most severe changes in the peripheral lower lobes
Affects the more distal bronchi and bronchioles, especially the vertical ones
Can affect just a single lung segment if caused by tumors or aspiration of a foreign body
Airways may be dilated up to 4x the normal size
Appear cystic and filled with mucopurulent secretions
In severe cases there can be inflammatory exudation within the walls of the airways that is associated with desquamation of the lining epithelium and lots of ulceration
For the rest of the tissue there may be pseudo stratification of the columnar cells or squamous metaplasia
Sometimes the necrosis can lead to abscesses
If chronic, there can be severe fibrosis and obliteration of the lumens
Bronchiectasis common pathogens
Staphylococcus (clusters), streptococcus (chains), enterics (gram negatives), anaerobic and microaerophilic pathogens (especially in pediatric populations), Haemophilus influenzae (vaccine), and pseudomonas aeruginosa
Bronchiectasis clincial course
signs and symptoms are often episodic and precipitated by URI
Persistent, severe cough
May be associated with morning or positional changes draining collected pus/secretions into the bronchi
Fever, orthopnea, dyspnea, and cyanosis
Abundant purulent sputum that is foul smelling and sometimes bloody
Complications bronchiectasis
Cor pulmonale
Brain abscess
Amyloidosis
Restrictive lung disorders
Chronic interstitial and infiltrative diseases
- pneumoconiosis
- interstitial fibrosis of unknown etiology
Chest wall disorders
-neuromuscular diseases (poliomyelitis, severe obesity, pleural diseases, kyphoscoliosis
Chronic interstitial pulmonary disease
signs and symptoms are often episodic and precipitated by URI
Persistent, severe cough
May be associated with morning or positional changes draining collected pus/secretions into the bronchi
Fever, orthopnea, dyspnea, and cyanosis
Abundant purulent sputum that is foul smelling and sometimes bloody
What happens in chronic interstitial pulmonary disease
L ong term development of cor pulmonale and 2° pulmonary HTN
May be difficult to distinguish in late stages because all result in scarring and gross destruction of the lung
End-Stage, or Honeycomb Lung
CXR: bilateral lesions that take the form of small nodules, irregular lines, or ground glass shadows that all indicate interstitial fibrosis
Fibrosing diseases
Ok
Idiopathic pulmonary fibrosis -MUC5B
Clinicopathologic syndrome of unknown cause with progressive interstitial pulmonary fibrosis and respiratory failure
Appears to occur in patients who are genetically susceptible to aberrant repair of recurrent alveolar epithelial cell injuries due to environmental exposures
Profibrotic response
Histologically, usual interstitial pneumonia (UIP) must be distinguished from other causes
UIP == nonspecific pattern of fibrosis shared with connective tissue diseases, chronic hypersensitivity pneumonia, and asbestosis
prototypic of restrictive lung disease
