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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
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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

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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
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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
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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
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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
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Syndromes with ciliary dysfunction
- 1. Primary Ciliary Dyskinesia
- 2. Cystic Fibrosis
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Primary Ciliary Dyskinesia
 - Situs Inversus
- Diffuse bronchiectasis
Mutation in CCDC39 --> dysfunction of cilia
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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
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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
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Measuring Mucociliary Clearance
- 1. Define lung boundaries
- -Xe133 inhalation

2. Tc99m-SC particle inhalation
- 3. Serial gamma camera tracks particle retention over time

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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
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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)
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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
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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
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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
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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)
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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
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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
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NETs correlate with lung function in CF
- -decades of exposure to NETs are deleterious
- -correlation between severity of disease and free DNA from NETs
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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
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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
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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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