L19 Lung Defense Mechanisms

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Author:
jknell
ID:
200846
Filename:
L19 Lung Defense Mechanisms
Updated:
2013-02-16 12:39:25
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Pulmonary II
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Pulmonary II
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  1. Why does the lung need defense
    -very large surface area (70x greater than skin)

    -thin barrier (0.3 um)

    Largest surface area in body exposed to external environment
  2. Inspired Particle Deposition
    -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
  3. Innate Immune System
    • -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
  4. Innate Immune System of the Lung
    • Upper Airways
    • -filtering of particles
    • -cough
    • -mucociliary system

    • Lower Airways/Alveoli
    • -macrophages
    • -neutrophils
    • -surfactant proteins (antimicrobial peptides)
    • -dendritic cells
    • -NK cells
  5. Cough
    • 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
  6. Mucociliary System
    • 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
  7. Syndromes with ciliary dysfunction
    • 1. Primary Ciliary Dyskinesia
    • 2. Cystic Fibrosis
  8. Primary Ciliary Dyskinesia
    • Situs Inversus
    • Diffuse bronchiectasis

    Mutation in CCDC39 --> dysfunction of cilia
  9. Cystic Fibrosis
    • -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
  10. PCD/Cystic Fibrosis Treatment
    • 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
  11. Measuring Mucociliary Clearance
    • 1. Define lung boundaries
    • -Xe133 inhalation

    2. Tc99m-SC particle inhalation

    • 3. Serial gamma camera tracks particle retention over time
  12. Antimicrobial Peptides
    • -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
  13. AMPs in CF
    -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)
  14. Alveolar Macrophages
    • -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
  15. Dendritic 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
  16. Natural Killer Cells
    • -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
  17. Pulmonary Surfactant
    • -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)
  18. Neutrophils
    • -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
  19. Neutrophil Extracellular Traps
    • -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
  20. NETs correlate with lung function in CF
    • -decades of exposure to NETs are deleterious
    • -correlation between severity of disease and free DNA from NETs
  21. Adaptive Immune Response
    • 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
  22. Adaptive Immunity Deficiency States
    • 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
  23. Vaccination
    • 1. Influenza
    • -elderly
    • -chronic lung disease

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

    • 3. Pertussis
    • -boosters in adolescents/adults

    • 4. HIB
    • -no more epiglottits

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