L19 Lung Defense Mechanisms

-very large surface area (70x greater than skin)

-thin barrier (0.3 um)

Largest surface area in body exposed to external environment

-laminar flow of air and branching of airways causes particle deposition

-the size of the particle determines where it is deposited



>10um settle high in the upper airway (nose)

5-10um settle in trachea and conducting airways

0.5-5um can reach the lung parenchyma (most bacteria fall in this range)

• **important for medication
• 

• -present in all multi-cellular organisms
• -immediately responsive
• -recognition not dependent on memory
• -activates the adaptive immune response
• -balance between eradication of pathogen and inflammatory damage to host

• Upper Airways
• -filtering of particles
• -cough
• -mucociliary system

• Lower Airways/Alveoli
• -macrophages
• -neutrophils
• -surfactant proteins (antimicrobial peptides)
• -dendritic cells
• -NK cells

• Four phases:
• 1. Irritation
• 2. Inspiration
• 3. Compression
• 4. Expulsion
• 

• Huff Cough:
• -inhale and hold breath to allow air to get around particles
• -exhale to maximum rapidly

• Deficiency States:
• 1. Muscular weakness (neuropathy, myopathy)
• -manual or mechanical cough assist
• -positioning
• 2. Pain
• -analgesics
• 3. Tracheostomy
• -suctioning
• -speaking valve

• Cilia
• -trachea to respiratory bronchioles are covered in cilia
• -cilia move in a wave like motion

• Mucus
• -covers the cilia
• -two layers: sol/periciliary layer (aqueous) and gel layer (viscous)
• 
• -rate of clearance may be regulated by extracellular nucleotides (mostly ATP)
• -transport to nasopharynx takes ~ 6h

• 1. Primary Ciliary Dyskinesia
• 2. Cystic Fibrosis

• 
• Situs Inversus
• Diffuse bronchiectasis

Mutation in CCDC39 --> dysfunction of cilia

• -mutation in Cl- channel
• -Na+ absorbed more rapidly to balance negative intracellular charge
• -water follows Na+

This causes the mucus to thicken and prevents the cilia from working

• Physical Adjuncts:
• -chest physiotherapy
• -postural drainage
• -"the vest"

• Mucus Hydration:
• -hypertonic saline
• -Ivacaftor (corrects genetic defect?)
• -Dornase alpha (dissolves DNA)

• PCD: physical adjuncts
• CF: physical adjuncts + mucus hydration

• 1. Define lung boundaries
• -Xe¹³³ inhalation
• 

2. Tc99m-SC particle inhalation

• 3. Serial gamma camera tracks particle retention over time
• 

• -produced by epithelial cells, neutrophils and other innate cells (PMNs most important source)
• -small, highly cationic
• -function by disrupting bacterial cell membranes
• -host cells are relatively resistant to AMPs

-lysozyme, lactoferrin, defensins, collectins

• Functions:
• -kill microbes direction
• -activate macrophages
• -recruit T cells (direct killing, activate humoral immunity)
• -angiogenesis

AMP activity requires bicarbonate

-increased NaCl in mucus is thought to inactivate defensins (not thought to be part of pathogenesis of CF anymore)

-defensins are sensitive to HCO3- (independent of pH)

• 
• -large cells
• -patrol luminal surface of alveoli
• -can phagocytose and digest inert inhaled particles
• -mediates surfactant homeostasis (stimulate GM-CSF)
• -detect foreign particles via PRRs
• -activate other inflammatory cells

• 
• -present in airway epithelium
• -samples fluid for foreign particles
• -microbes activate recruitment of more DCs to airways
• -APCs (stimulate innate and adaptive immune systems)
• -important in clearing viral pathogens

• 
• -rapid response
• -kill mics without prior sensitization
• -lack surface markers of B and T cells
• -target virally transformed cells lacking markers of differentiation
• -important in tumor surveillance

• 
• -4 types of surfactant proteins (SP-A, SP-B, SP-C, SP-D)
• -B and C are important for surface tension
• -A and D are important for surfactant regulation and antimicrobial action (pattern recognition receptors)

• Antimicrobial Functions:
• 1. Aggregation of pathogens
• 2. Direct lysis of bacteria
• 3. Increased phagocytosis of mics
• 4. Increased phagocytosis of dead cells
• 5. Regulation of mediator production (can signal T cells)

• 
• -central to inflammatory response
• -workhorse of innate immune system
• -multiple anti-microbials and signaling functions
• -sit in the pulmonary capillary surface ready to enter the lungs

• NETs
• Primary granules
• Specific and Tertiary granules

• 
• -extracellular expulsion of nuclear and cytoplasmic granule material
• -components: DNA, histones, AMPs, MPO
• -trap and kill fungi and bacteria
• -implicated in pathogenesis of autoimmune disease

• -decades of exposure to NETs are deleterious
• -correlation between severity of disease and free DNA from NETs

• Humoral (B cells)
• -agglutinate and opsonize bacteria
• -enhance clearance, endocytosis, C' mediated lysis

• Cell-Mediated (T cells)
• -modify Ab production
• -recruit other immune cells
• -important for intracellular pathogens

• Adaptive Immunity in Lung:
• -lymphoid tissue present from nose to parenchyma
• -true LNs along trachea at carina and hila
• -BALT along conducting airways
• -IgA in nasopharynx and upper airways
• -IgG in lower airways and airspaces
• -antibodies from resident plasma cells

• 1. Humoral
• -acquired or congenital hypogammaglobulinemia
• -increased risk of bacterial pneumonia

• 2. Cellular
• -systemic corticosteroids (latent or acute viral/fungal dissemination)
• -HIV/Lymphoma (pneumocystis, CMV)
• -Cancer chemotherapy
• -Post-transplant immunosuppression

• 1. Influenza
• -elderly
• -chronic lung disease

• 2. Pneumococcus
• -elderly
• -chronic lung disease
• -asplenia

• 3. Pertussis
• -boosters in adolescents/adults

• 4. HIB
• -no more epiglottits