Overview

• Characterized by inflammation and/or fibrosis in the lung tissue.
• Pulmonary restriction with reduced total lung capacity, forced vital capacity, and forced expiratory volume at one second.
• Signs and symptoms:
  – Progressive dyspnea; most patients initially experience dyspnea only upon exertion but, over time, develop difficulty breathing even during rest.
• Dry, non-productive cough is common, and, some patients will present with digit clubbing.
• Chest x-rays often show opacities or other abnormalities.
• Complication of interstitial lung disease is pulmonary arterial hypertension.
• Diagnosis: Due to the non-specific and overlapping signs and symptoms diagnosis is often difficult, and often involves specialists from multiple fields who can integrate findings from chest imaging, pulmonary function tests, clinical exams, and histological sampling.
• Treatment varies, and is often targeted at the underlying disease; in some cases, anti-fibrotic drugs, such as pirfenidone, are helpful.

Histopathology

• We draw a healthy alveolar duct opening to alveolar spaces, which are separated by alveolar septi.
  – In healthy lungs, the alveolar walls are compliant and expand upon inhalation to facilitate gas exchange with the pulmonary capillaries.
• Interstitial lung disease develops when, in response to various stimuli, fibroblasts and myofibroblasts proliferate in the ducts and sacs.
• These proliferating cells promote extracellular matrix deposition and collagen accumulation.
• This leads to alveolar septal thickening; if left unchecked, fibrosis can develop.
• The thickened alveolar membranes are stiffer and cannot expand upon inhalation, which inhibits gas exchange.

TYPES OF INTERSTITIAL LUNG DISEASE

EXPOSURE

Let’s begin with interstitial lung diseases that develop in response to exposure to external agents.
Occupational

• Asbestosis and silicosis develop when pulmonary macrophages ingest asbestos fibers or silica dust, which triggers the histological changes we just drew.
  – Scarring is diffuse, and ground glass reticular opacities and pleural plaques are seen on chest x-ray.
• Coal worker’s pneumoconiosis, aka, “black lung” occurs when pulmonary macrophages ingest coal dust.
  – Numerous small nodular opacities are visible in chest x-rays.
• Hypersensitivity pneumonitis is a type III or mixed type III/type IV hypersensitivity that results from exposure to specific environmental triggers.
  – Farmer’s lung is caused by exposure to molds that grow in hay or other feed grains; additional examples include “bird fancier’s lung” and “humidifier lung.”

Drugs

Over 400 drugs can cause interstitial lung disease.

• Antibiotics (such as amphotericin B)
• Anti-inflammatories (Aspirin and NSAIDS)
• Cardiovascular medications (including ACE-inhibitors and beta-blockers)
• Chemotherapy drugs

Infections

• Examples include aspergillosis, histoplasmosis, and mycobacterial infections.

SYSTEMIC DISORDERS

Connective Tissue Disorders

Many connective tissue disorders are immune or autoimmune pathologies with excessive collagen deposition or mucus reduction; thus, when the lungs are involved, restriction occurs.

• Some key examples include: Systemic sclerosis, rheumatoid arthritis, systemic lupus, and sjogren’s syndrome.

ANCA vasculitides (ANCA = Anti-Neutrophilic Cytoplasmic Autoantibodies)
Remind ourselves that these disorders include: Granulomatosis with polyangiitis (aka, Wegener’s disease), eosinophilic granulomatosis with polyangiitis (aka, Churg-Strauss syndrome), and, microscopic polyangiitis.

Granulomatous lung diseases

• Granulomatous-lymphocytic interstitial lung disease & sarcoidosis.

IDIOPATHIC INTERSTITIAL PNEUMONIAS

The causes of these diseases are unclear, but each is associated with characteristic histological and clinical features; diagnosis is often based on exclusion.

Additional images

• Idiopathic pulmonary fibrosis is the most common idiopathic interstitial pneumonia.
  – It is characterized by a histological pattern called “usual interstitial pneumonia;” this comprises patches of honeycomb patterns and areas of fibroblasts and dense collagen.

• Nonspecific interstitial pneumonia is associated with younger women with no history of smoking; this type is sometimes associated with immune or connective tissue disorders.
  – The histological pattern comprises homogenous areas of fibrosis or cellular inflammation (not honeycomb).

• Desquamative interstitial pneumonia develops in cigarette smokers older than 30.
  – Characterized by diffuse inflammation with pigmented macrophages in the alveoli. The brownish pigments in the macrophages are iron-rich granules commonly found in cigarette smokers’ lungs.

• Respiratory bronchiolitis-associated interstitial lung diseasealso affects smokers older than 30 and is characterized by pigmented macrophages; however, in these patients, inflammation is patchy.

• Cryptogenic organizing pneumonia is a flu-like illness characterized by collections of collagen, fibroblasts, and myofibroblasts that plug the small airways and alveolar ducts, and alveoli are inflamed.
  – Be aware that cryptogenic organizing pneumonia was formerly known as bronchiolitis obliterans with organizing pneumonia.

• Lymphocytic interstitial pneumonia* is characterized by lymphocytes and plasma cell infiltration into the alveoli and septi.

• Acute interstitial pneumonia is characterized by diffuse alveolar damage and thickening, edema, and inflammatory cell infiltration, with possible hyaline membranes forming in the septa.
  – Acute interstitial pneumonia can quickly lead to respiratory distress.
  – Be aware that acute interstitial pneumonia is sometimes called Hamman-Rich syndrome.

Others:

• Lymphangioleiomyomatosis: Genetic defect; Characterized by smooth muscle cell growth throughout the lungs, kidney, and lymphatic system.
  – Almost always in women 30+ years old.
  – Often associated with tuberous sclerosis complex (an inherited syndrome).
  – Often associated with recurrent pneumothorax.
  –

• Pulmonary alveolar proteinosis
  – Lipoprotein surfactant accumulates in the alveoli (stains periodic acid-Schiff positive).
  – Can be hereditary or autoimmune.

• Langerhan’s cell histocytosis
  – Langerhans cells accumulate in the lungs.
  – Associated with cigarette smoking.

• Pleural parenchymal fibroelastosis
  – Fibrosis that is originally predominant in upper lobes, may progress throughout lung.

Overview

Bronchiectasis is a chronic, heterogeneous disorder caused by repeated bouts of infection and inflammation that cause permanent dilation of the medium and medium-large airways.
– Damage can be focal or diffuse, depending on the cause and extent of the damage.
– Etiologies:
Obstruction, which causes focal bronchiectasis, and can be due to tumor masses or foreign bodies in the bronchi.
Infections, often bacterial; common pathogens include Pseudomonas aeruginosa, Haemophilus influenzae, and Non-tuberculosis mycobacteria.
Immune deficiencies
Autoimmune disorders; for example, bronchiectasis is associated with inflammatory bowel disease and rheumatoid arthritis.
Allergic bronchopulmonary aspergillosis; as its name suggests, this form of bronchiectasis is caused by an allergic reaction to the common mold aspergillus;
Genetic conditions, including cystic fibrosis, alpha-1-anti-trypsin deficiency, and primary ciliary dyskinesia (aka, Kartagener syndrome) – these disorders are associated with increased mucus production, neutrophilic damage, and impaired muco-ciliary functions, respectively.
**Asthma and/or COPD
– Many cases of bronchiectasis are idiopathic.

Bronchiolitis is a common affliction of children younger than two years of age; it occurs as result of respiratory infections.

BRONCHIECTASIS:

• Most patients have cough with prominent sputum production.
  – The sputum itself is often described as thick and “tenacious.”
• Hemoptysis may also occur, and is the result of airway neovascularization and rupture.
• Lung crackles and rhonchi
• Some patients wheeze
• Historically, bronchiectasis was associated with digit clubbing, in which the ends of the digits are enlarged and rounded; however, this is less commonly reported, today. The mechanistic link between bronchiectasis and digit clubbing is uncertain.
• Some patients have so-called “dry” bronchiectasis – this is often associated with nontuberculous mycobacterial infection, and is characterized by less sputum production.
• Exacerbations are defined as worsening symptoms that last two days or longer, and require changes in treatment approach.
  – Exacerbations are especially problematic because they cause additional bronchial damage.
• Complications can lead to hypoxemia, due to airway obstruction, and even pulmonary hypertension and right heart failure.
• Treatments:
  – Airway clearance techniques
  – Exercise
  – Macrolides and other antibiotics
  – Hyperosmolar and mucolytic agents that transform mucus to facilitate clearance
  – Anti-inflammatory drugs

Pathogenesis: A Vicious Cycle

• Impaired mucociliary clearance and retention of airway secretions, which creates an environment vulnerable to chronic infections.
• Chronic infections results in chronic inflammation with neutrophilic and T-cell infiltration.
• These inflammatory cells release cytokines that cause tissue destruction and airway remodeling
• Over time, this degradation of the bronchial wall produces dilation.
• And, chronic infection and inflammation further impair mucociliary clearance.

Pause for a moment and consider where and how some of the causes of bronchiectasis promote this cycle: cystic fibrosis increases mucus production; infection, especially by antibiotic-resistant bacteria, cause chronic and harmful inflammation, and immune deficiencies fail to clear infections effectively.

• Despite the fact that medium-sized airways are dilated in bronchiectasis, they can also become obstructed by recurrent inflammation and infection and mucus accumulation.
• Furthermore, smaller, downstream airways, which significantly impact airflow, can become obstructed by the inflammation and infections.
  – Thus, the complications we discussed earlier, including hypoxemia and right heart failure, can occur.

###Bronchiolitis

• Common in children under two years of age.
• It is most often caused by RSV, though rhinovirus and parainfluenza virus can also cause bronchiolitis.
• Pathogenesis: bronchiolitis occurs when the small bronchial tubes become inflamed, necrotic, and, subsequently, narrowed by mucus and debris.
  – As a result, that some alveoli collapse because air cannot be delivered to them, whereas low-oxygen air is trapped in other alveoli.
• Signs and symptoms:
  – Infants can experience fever, congestion or runny nose, coughing, and wheezing. Indicate that cyanosis, particularly of the lips and nail beds, can occur as the result of reduced oxygen levels.
  – Other signs of bronchiolitis include: rapid, shallow breathing and/or apnea, with wheezing and crackling.
  – Infants struggling to breath may grunt and, as a result of accessory muscle involvement and straining, retractions may be observed – look for “sucking in” of the skin around the base of the neck as the infant struggles to bring in air.
  – Due to congestion and obstructed breathing, infants may also have difficulty bringing in foods and liquids, which can lead to dehydration.

Overview

• A heterogeneous chronic disease of the conducting airways.
• Characterized by intermittent and mostly reversible periods of bronchial obstruction, with bronchial hyper-reactivity, excessive mucus, and airway remodeling; in contrast, recall that COPD is characterized by constant, irreversible airway obstruction.
• Asthmatic patients experience episodes of cough, wheezing, dyspnea, and feelings of chest tightness.
• Characterized by increased total lung capacity because air is trapped in the lungs.
• The ratio of forced expiratory volume in one second to forced vital capacity is normal or low.
• The diffusing capacity of the lungs for carbon monoxide is normal or elevated.
• Ventilation to perfusion mismatches occur, which can lead to hypoxemia.
• Asthma is a heterogeneous disease with different etiologies and characteristics, and there are different ways to classify asthma types
  – Historically, asthma has been classified based on phenotypes, which are the observable characteristics – such as by the presence or absence of eosinophils.
  – Many researchers are now shifting towards classification based on endotypes, which are based on the pathophysiologic mechanisms that drive types of asthma – such as whether high levels of type 2 inflammation is involved.
• Diagnosis of asthma can include: pulmonary function tests (spirometry), methacholine bronchial challenge tests, and allergy tests.
• Treatments for asthma can be broad-based or more targeted, depending on the asthma type.

Types of Asthma

We organize these based on presence of granulocytes and the type of inflammation.

Eosinophilic asthma with high levels of type-2 inflammation

This group includes the most thoroughly studied subtypes of asthma.

• Type-2 inflammation is due to an imbalance towards T-helper 2 cells and Type-2 innate lymphoid cells and their cytokines (specifically, IL-4, IL-5, and IL-13) which promote IgE production from B cells.

• Early Onset with Allergy: because allergens are the triggers for asthma attacks, this subtype is sometimes called “Extrinsic asthma.”
  – Asthma attacks are IgE-mediated, and patients often have other allergies and history of rhinitis and atopic dermatitis. Click to review Hypersensitivity Type 1
  – Tends to be familial, is associated with early childhood respiratory viral infections (especially RSV and rhinovirus), and, is most common in boys.
  – Biomarkers include elevated eosinophils and serum IgE.
  – Common triggers include house dust mites, mold, pets, and pollen.

• Late-onset without atopy
  – Patients have fewer allergies, but often present with more severe asthma.
  – Often co-exists with chronic rhinosinusitis and nasal polyps.
  – Not familial, and tends to occur most often in adult females.
  – Biomarkers include elevated eosinophils, and, in a sub-set of patients, elevated levels of Staphylococcus aureusendotoxin-specific IgE.
  Be aware that, although most patients do not have elevated levels of IgE, it is thought that localized IgE in the airways occurs.
• Key triggers in this group include air pollution, especially diesel gas fumes and other irritants, as well as respiratory infections.

• Aspirin-exacerbated asthma (aka, aspirin-exacerbated respiratory disease – AERD)
• Form of asthma triggered by aspirin – it is often severe, and typically occurs in adults
  – Thus, some consider this to be a sub-sub-type of late-onset asthma.
  – Aspirin-exacerbated asthma is due genetic abnormalities that lead to dysregulation of arachidonic acid metabolism.

Next, let’s consider some other types of asthma.

Neutrophilic, type-2-low asthma

• Characterized by elevated levels of the cytokine IL-17 and oxidative stress.
• Neutrophilic asthma is usually adult-onset and is often severe.
  – Resistant to corticosteroids.
• Key at-risk populations include: smokers, obese people, and elderly people.

Mixed granulocytic asthma

• Characterized by elevated levels of T helper 2 and T helper 17 cytokines.

Paucigranulocytic asthma

• Characterized by non-inflammatory (or low inflammatory) changes in the bronchi: remodeling and hyper-reactivity.

Two additional asthma phenotypes that can overlap with those already listed:
Occupational, aka, work-related asthma

• Develops in response to exposure to workplace allergens or irritants (and, because it is occupation-related, tends to develop in adulthood).
  Exercise-induced/exacerbated asthma
• Triggered by exercise.
• Although the exact mechanisms are unclear, it is thought that exercise-related evaporation and water loss from the airway epithelia causes injury that leads to upregulation of pro-inflammatory mediators.

Comparison with healthy bronchi.

• Smooth muscle overgrowth, which contributes to hyper-reactivity and constriction of the airways.
• Possible inflammation and fibrosis with migration of eosinophils and/or neutrophils in the wall of the airway (depending on the type of asthma).
• The basement membrane is thickened.
• Respiratory epithelium displays goblet cell metaplasia.
• Excess mucus further narrowing the airway so that the lumen is much smaller than normal.
• Other hallmarks of asthma may be seen in the sputum:
  – Curschmann spirals are mucus plugs that comprise desquamated airway epithelial cells.
  – Charcot-Leyden Crystals are crystals formed from eosinophil proteins.

Treatments

Step-wise approach to treatment

• Short-acting beta-antagonists, such as Albuterol, are provide for quick relief during asthma attacks; they relax the smooth muscle lining the bronchi.
• Long-acting beta-antagonists, such as Salmeterol, may be used longer-term in conjunction with other drugs.
• Inhaled corticosteroids, such as beclomethasone, suppress airway inflammation and are first-line therapy for long-term asthma management.
• Leukotriene antagonists, such as montelukast, also reduce bronchoconstriction and inflammation, and are especially useful in exercise- and aspirin-exacerbated asthma.
• Anticholinergics, such as Ipratropium and Tiotropium, produce smooth muscle relaxation in the bronchi.
• Anti-IgE antibodies, such as Omalizumab, are effective in allergic asthma.
• Anti-IL-5 antibodies, such as Mepolizumab, are useful in severe eosinophilic asthma.
• Mast cell inhibitors, such as Cromolyn, prevent mast cells from releasing inflammatory mediators that lead to bronchospasm.
• Oral corticosteroids, such as prednisone, are used in severe asthma to reduce inflammation; because oral corticosteroids can have serious side effects, they are typically used for acute attacks.

Overview

• COPD is characterized by chronic, progressive, irreversible air flow obstruction
  – Leads to high lung volumes (functional residual capacity, residual volume, and total lung capacity).
• As a result of airway obstruction, the ratio of Forced Expiratory Reserve Volume in 1 second to Forced Vital Capacity is reduced
• COPD includes Chronic bronchitis, small airway disease, and emphysema.
• Asthma-COPD overlap syndrome: Symptoms of airway hyper-reactivity and airway obstruction.
• COPD can lead to V/Q mismatch, hypoxemia, pulmonary hypertension, and right heart failure (cor pulmonale).
• It is estimated that approximately 16 million people in the US have diagnosed COPD, and many are undiagnosed;.
• COPD is a leading cause of death worldwide.
• Previously thought of as a man’s disease, we now see high rates of COPD in both men and women; patients are typically over 65 years of age and are current or former smokers.
• Key risk factors are smoking, air pollution (including indoor pollution, such as the smoke from burning organic fuels for heating), and, genetics.
  – Alpha-1 antitrypsin deficiency is a known genetic cause of emphysema; this defect allows excess elastase in the lungs, which degrades alveoli.
• COPD is not curable
• Treatments are meant to relieve symptoms and slow progression; in addition to quitting smoking and limiting exposure to second hand smoke, patients may be prescribed bronchodilators, steroids, respiratory therapy, or supplemental oxygen. Prevention of respiratory infections via flu and pneumococcal vaccines are also important, as they prevent COPD exacerbations.
• Surgery may be appropriate for some patients.

Signs & Symptoms

COPD is the result of air trapping in the lungs; two key causes of air trapping are:
– Reduced elastic recoil in the lung parenchyma (which occurs in emphysema).
– Increased airway resistance (which occurs in chronic bronchitis and small airway disease, aka, SAD).

• Be aware that most patients have a combination of these disorders, which is why signs and symptoms often overlap – thus, the familiar concept of “pink puffers” vs. “blue bloaters” is an oversimplification.

• Decreased breath sounds, which some describe as “distant” sounds.
• Cough, sputum production, wheezing, and dyspnea.*
• Rhonchi; recall that rhonchi are low-pitched rattling sounds produced by airway secretions.
• Patients who are having difficulty breathing may adopt specific behaviors, such as pursed-lip breathing or tripod position:
  – Pursed-lip breathing slows down the breathing and increases airway pressure; incidentally, learning how to do pursed-lip breathing is also a component of respiratory therapy.
  – In the tripod position, patients brace their upper against their legs or the arms of a chair; this position helps to take some of the work out of breathing.
  – Cyanosis of the lips and nail beds, which are signs of hypoxia.
• Specific morphological changes may also be apparent; these are due to high lung volumes and hyperinflation of the chest.
  – Chronic hyperinflation leads to flattening of the diaphragmand shortening of its muscle fibers, which renders it less mechanically capable.
  – Thus, accessory respiratory muscles must do more work (including the scalenes, sternocleidomastoid, trapezius, abdominal muscles). It may be possible to palpate these hypertrophied muscles.
  – Many patients develop a “barrel-shaped” chest, in which the anterior-posterior diameter of the chest becomes larger.
  – Hoover’s respiratory sign is a pronounced inward movement around the costal margin during inspiration.
• Weight loss and muscle wasting, especially of the lower extremities.
• Peripheral edema
  – Edema is a potential manifestation of the systemic effects of COPD, which can include right heart failure and/or reduced renal flow.
• Be aware that COPD is associated with various cardiac, renal, and metabolic co-morbidities.
• Markers of systemic inflammation are often elevated.

• Exacerbations are defined as acute bouts of worse symptoms that require changes in treatment.
  – Exacerbations are often due to bacterial or viral infections, or exposure to air pollution.

Pathologic Changes

• Smoking leads to pulmonary dysfunction via multiple mechanisms:
  – Increased mucus production, impaired ciliary clearance, oxidative stress, and inflammatory cell recruitment.
• We draw the lower respiratory system, so that we can show how different portions are affected by these mechanisms, and we label the bronchi and bronchioles of the conducting zone, and the respiratory bronchioles and alveoli of the respiratory zone.

Chronic Bronchitis affects the bronchi, which are the larger airways of the lungs.
– Clinically defined as a chronic cough with sputum production that lasts for three or more months in two consecutive years.

• We show the histopathology of chronic bronchitis, from outermost to innermost:
  – For context, show some hyaline cartilage
  – Mucosa is characterized by hypertrophy and hyperplasia of mucous glands
  – Smooth muscle is also hypertrophied
  – Submucosa is infiltrated by inflammatory cells (specifically, CD8+ T-cells, neutrophils, and macrophages)
  – Respiratory epithelium has excessive goblet cells and possible squamous cell metaplasia
  – Respiratory cilia are impaired
  – The mucus, which is normally thin and runny, becomes abundant and viscous, thanks to mucus gland hyperplasia.
• Cumulatively, these changes produce a thicker bronchial wall, with limited ability to clear debris; thus, airway obstruction can occur.

Small Airway Disease affects the bronchioles.

• Small changes in bronchiole airflow have influence over total airflow, so this is where the most significant airway obstruction occurs.
• Small airway disease is characterized by mucus plugging, inflammation, and airway remodeling, which comprises fibrosis and thickening; together, these factors narrow the bronchiole lumen.
• Variation in V/Q can result from airway obstruction that leaves some alveoli under-ventilated and other alveoli holding trapped air.

Emphysema affects the respiratory bronchioles and alveoli.

• Inflammatory cells, which are recruited in response to cigarette smoke and other irritants, secrete elastase, which is an enzyme that breaks down alveolar walls.
  – Alpha-1 antitrypsin is a protective protein that inhibits elastase, which is why individuals with alpha-1 antitrypsin deficiency are more susceptible to emphysema.
• Oxidative stress from smoking damages pulmonary collagen and elastin.
• Elastase and oxidative damage break down the walls of the respiratory bronchioles and alveoli.
• Thus, there is less elastic recoil; thus, there is a reduction in the driving force to expel air during expiration.
• There is also loss of structural support, so the alveoli and alveolar ducts are prone to collapse and trap air.
• With the loss of respiratory zone structures, there is less surface area for gas exchange.*
• Because of variation in the disease process, emphysema is associated with variation in V/Q.

Overview

• Acute respiratory distress syndrome (ARDS) occurs when the alveoli fill with fluid, which impairs gas exchange.
• Characterized by acute dyspnea, hypoxemia, and pulmonary infiltrates.
• Can lead to reduced lung compliance, increased pulmonary dead space, increased risk of pneumothorax, and pulmonary hypertension.
• ARDS has a mortality rate of approximately 40%.
• Treatment for acute respiratory distress syndrome requires treatment of the underlying causes.
• Mechanical ventilation restores airflow, but beware of potential complications, including: volutrauma (overdistention of the alveoli), alectectrauma (alveolar strain from repeated opening and closing), and, biotrauma (from migration of pro-inflammatory molecules and pathogens).
• Treatment includes fluid management measures, such as diuretics, to reduce left atrial filling pressure; some also recommend the use of neuromuscular blockades.
• Newborn respiratory distress syndrome (aka, infant respiratory distress syndrome, respiratory distress syndrome of the newborn) occurs when there is inadequate production of surfactant by premature lungs, leading to alveolar collapse; thus, treatment includes administration of synthetic surfactant and oxygen support. The risk of neonatal respiratory distress correlates with the degree of prematurity.

Pathophysiology: 3 stages
Exudative Phase: The initial response to injury, and occurs within the first 7 days after exposure.

• Inflammation damages the capillary endothelium and alveolar epithelium, and increases the permeability of these layers. We show neutrophils and their pro-inflammatory cytokines, but be aware that other cells of the innate immune system also play a role in barrier injury.

• Protein-rich fluid, activated neutrophils, and other pro-inflammatory mediators and cellular debris pass through the barrier and fill the alveolus.
• These infiltrating proinflammatory mediators damage the epithelial lining of the alveolus, leaving the basement membrane “denuded.”
• Furthermore, due to the loss of alveolar epithelial cells, surfactant production and fluid resorption is inhibited,which compounds fluid retention.
• Hyaline membranes from along the denuded basement membranes; these are formed by accumulating cellular debris and fibrin.
• The coagulation cascade is triggered by capillary endothelial damage, which leads to the formation of microthrombi in the vessels.
• As a result of these pathological processes, gas exchange is inhibited, dead space is increased, pulmonary hypertension occurs, and lung compliance decreases.

Proliferative Phase: barrier repair and fluid resorption and occurs days 7-21 after exposure to pulmonary injury.

• The alveolar epithelium and capillary endothelium barriers are re-established.
• Thus, surfactant production and fluid reabsorption resume
  – Epithelium sodium channels and aquaporins are inserted in the alveolar epithelium, and move fluids to the interstitium.
• Macrophages and lymphocytes remove apoptotic and inflammatory mediators, thus reducing further harm to the epithelia.
• As part of the healing and rebuilding process, fibroblasts and other interstitial cells proliferate to form a provisional extracellular matrix, which will eventually be removed by matrix metalloproteinases.
• However, in some individuals, pro-inflammatory and fibrotic forces overwhelm the healing and clearance process.

Fibrotic Phase: Fibrosis

• Extensive epithelial damage trigger over-proliferation and differentiation of fibroblasts and deposition of collagen, which leads to tissue fibrosis and destruction of the microvasculature.
• Thus, pulmonary dysfunction continues.

Causes of ARDS

• Direct and indirect causes of lung injury lead to acute respiratory distress.
• The most common causes are pneumonia (direct) and sepsis(indirect)
  – Account for more than half of all ARDS cases.
• Additional Direct Causes:
  – Aspiration of gastric contents
  – Pulmonary contusion
  – Near drowning
  – Vaping.
  Be aware that lung injury caused by vaping is sometimes called “EVALI” – “E-cigarette or Vaping Associated Lung Injury”, and is particularly associated with vaping fluids containing Vitamin E acetate (Vitamin E acetate is used in THC vaping products).
• Additional Indirect Causes:
  – Trauma
  – Repeated blood transfusion
  – Pancreatitis
  – Drug reactions or overdoses (ex: various narcotics, aspirin, tricyclic antidepressants).

Berlin Definition of ARDS
Establishes diagnostic criteria

• Onset of signs and symptoms must be *within the last 7 days of known clinical insult, with new or worsening symptoms during the last week.
• Chest X-ray or CT will show bilateral opacities consistent with pulmonary edema.
• Respiratory failure cannot be otherwise fully explained by cardiac failure or fluid overload.
• Presence of acute hypoxemia.
  – Based on the ratio of the partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FiO2) (assessed while the patient is on a ventilator with a positive-end expiratory pressure (PEEP) of 5 or greater cm H2O).
  – Hypoxemia severity can be categorized as mild (201-300 mmHg); moderate (101-200 mmHg), or severe (100 mmHg or less).

DEFINITIONS

Bohr effect

• Low pH enhances hemoglobin oxygen dissociation

2, 3 Bisphosphoglycerate (BPG)

• Molecule localized in red blood cells
• Decreases hemoglobin’s oxygen affinity

DISSOCIATION CURVE

• % oxygen saturation vs. oxygen partial pressure (torr)
• Cooperative binding produces sigmoidal binding curve

Bohr Effect

• Decrease in blood pH shifts curve to the right
• Hemoglobin requires greater pO2 in peripheral tissues to reach 50% saturation
• Lowering pH decreases hemoglobin’s oxygen affinity

2,3 BPG

• Hemoglobin without 2,3 BPG: shifts curve to the left (hyperbolic like myoglobin)
• Adding 2,3 BPG: shifts curve back to the right.

BOHR EFFECT

Beta subunit

• Aspartate (-) and histidine (+)

T-form: histidine pKa = 8.0 (side chains close to each other)

• T-form favored when blood pH –> has a high affinity for H+

R-form: histidine pKa drops to 7.1 (side chains move apart)

• Histidine loses H+
• R-form favored when blood pH is high and H+ concentration is low

Carbon dioxide

• CO2 + H2O –> H2CO3 (carbonic acid) –> HCO3- (bicarbonate) + H+ (reversible)
• Carbonic anhydrase catalyzes carbonic acid formation
• Carbonic acid spontaneously loses proton to form bicarbonate
• Bicarbonate = blood buffer
• Increase in CO2 –> lowers blood pH –> favors T-form hemoglobin

Carbaminohemoglobin: CO2 binds N-terminal amino acids in hemoglobin

2,3 BPG

• Has strong negative charge: binds central cavity in hemoglobin
• Stabilizes the T-form (only binds T-form)

CARBON MONOXIDE

• Binds iron center with 220 times the affinity of O2 (irreversible)
• Permanently increases oxygen affinity of remaining heme groups for oxygen
• Decreases oxygen release in peripheral tissues

CLINICAL CORRELATION

Acetazolamide

• Carbonic anhydrase inhibitor used to treat altitude sickness
• Increases bicarbonate excretion by kidneys
• Makes blood more acidic, promotes oxygen release in peripheral tissues

High altitude conditions

• Individuals adapted to high altitude produce more 2,3 BPG
• Favors T-form hemoglobin and O2 release: more efficient O2 delivery

Tobacco smoke

• Smokers have elevated blood CO: hinders O2 delivery
• Can produce tissue hypoxia

Definitions

Cooperative binding

• Describes unique interactions between heme groups in hemoglobin
• Small movement of heme group propagates through hemoglobin’s 3D structure

HEMOGLOBIN STRUCTURE

R-form (relaxed)

• Alpha-alpha interactions: weak ionic and H-bonds form salt bridges
• Beta-beta interactions: no interactions; move apart upon oxygenation
• Alpha-beta dimers: strong hydrophobic interactions within each dimer

T-form (tense)

• 3D structure changes between oxygenated and deoxygenated states

HEME SITE

T-form (tense)

• Heme site: when O2 leaves, iron center moves out of porphyrin plane & proximal histidine moves away from iron center
• Small movement in heme group makes O2 binding unfavorable

SALT BRIDGES

• Salt bridges break and reform upon oxygen binding –> peptide wiggle-room
• Alpha chain salt bridges:
  – Alpha1: arginine carboxy terminus (-) and arginine side group (+)
  – Alpha2: lysine (+) and aspartate (-)
• Salt bridges regulate cooperativity: iron centers move into porphyrin planes

DISSOCIATION CURVE

• % oxygen saturation vs. oxygen partial pressure (torr)
• Cooperative binding produces sigmoidal binding curve
• After hemoglobin reaches 50% saturation: saturation increases rapidly (steepest point of curve)
• Hemoglobin O2 affinity rapidly increases at half saturation

Globular proteins

• Compact proteins that are approximately spherical in shape

Hemoproteins

• Specialized proteins that have prosthetic heme group

Prosthetic groups

• Non-protein molecules that are essential to biological function

HEME GROUP STRUCTURE

• Porphyrin ring with iron center (Fe2+)

Fe2+ coordinates 6 bonds:

• 1-4. Four planar nitrogen atoms (of porphyrin ring)
  5. Proximal histidine
  6. Oxygen

MYOGLOBIN

• Skeletal and cardiac muscle
• Reservoir for oxygen
• Single polypeptide with 8 alpha helix segments
• One heme group
• Distal histidine holds oxygen in place

HEMOGLOBIN

• Red blood cells
  – Supplies body’s tissues with oxygen
• 4 polypeptides (instead of one): each subunit resembles myoglobin structure
  – Tetramer: with 2 alpha-beta dimers
• Strong hydrophobic interactions: stabilize alpha-beta dimer
• Weak ionic and H-bonds: between dimers

T-form hemoglobin

• “Taught” or “tense” form: polypeptides restricted in movement
• Deoxygenated form: oxygen affinity is low

R-form hemoglobin

• “Relaxed” form: weaker ionic and H-binds between dimers
• Oxygenated form: oxygen affinity is high

COOPERATIVE BINDING

• Conformational change between T-form and R-form hemoglobin
• Myoglobin does not exhibit cooperative binding: only one oxygen binding site
  – One oxygen binds hemoglobin subunit
  – Binding disrupts inter-dimer bonds: causes conformational change
  – Change in 3D structure increases oxygen affinity of remaining subunits

DISSOCIATION CURVE

• % oxygen saturation vs. oxygen partial pressure (torr)
• Cooperative binding produces sigmoidal binding curve
• pO2 in body’s tissues: 30 torr
• pO2 in lungs: 100 torr

Hemoglobin

• Half saturated at 30 torr (body’s tissues): responds to O2 availability

Myoglobin

• Hyperbolic curve (simpler binding pattern corresponds to single heme)
• High affinity for O2
• Binding properties correspond to role in oxygen in storage (not oxygen delivery)
• Early curve: exercising muscle; plateau: muscle at rest

CLINICAL CORRELATION

Fetal hemoglobin

• Dissociation curve to the left of adult hemoglobin
• Greater affinity for O2: O2 transfer from maternal hemoglobin to fetus