L15 Lung Defense Mechanisms Flashcards
You visit an 80year old NZ European woman in a private hospital with the GP you are shadowing. she has a fever and is coughing up purulent sputum. She is in the private hospital because of dementia and has been a resident for the past 3 years. She is an ex-smoker. A mobile chest radiograph taken in the private hospital shows ‘confluent shadowing in the left lower lobe and a left-sided pleural effusion)
Pneumonia
confirmed by chest radiograph showing shadowing
Pneumonia presentation
Imbalance between
- Defence mechanisms
- Microbial Insult
4x Lung Defence mechanisms
- Need to preserve “sterile” environment at alveolar level
- “Direct” communication with the external environment
- Numerous potential “insults”
- High ventilation rate (5Lrest, 20L exercise), particularly during exertion
Issues with lung transplantation
- “Direct” communication with the external environment
- Numerous potential “insults”
- leads to issues with lung transplantation
- vs solid organs enclosed in body
- greater rate of rejection and infection
Microbiome
Microbiome: totality of microbes; bacteria, viruses, fungi.
New culture-independent technologies
Community profiling (based on amplification of 16S rRNA – bacteria)
Shotgun Metagenomics. (Human Microbiome Project)
-produce mega data
Airway Microbiome
LRT(Lower Respiratory Tract) is not sterile.
- Healthy microbiome protects against disease
- Altered microbiome (dysbiosis) in diseases (causes inflammation, damage and overt disease); spatial and longitudinal assessment of microbiome
- Aberrant microbiome – inflammation – disease
- Cross-talk between lung and gut microbiome (lung is outgrowth of foregut) (occurs from neonatal period and continues)
- Effects of treatment on microbiome ; antibiotics and other
- Role of modification ; probiotics (restoration of gut/lung microbiome)
Sterile nature of Lower Respiratory tract
Not sterile
Have to go through upper respiratory tract difficult to sample whilst avoiding contamination
Upper airways defence mechanisms
- Effective coordinated swallowing mechanism (oesophagus not trachea)
- Protection of lower airway by epiglottis and glottis
- Cough
- Sneeze
- deranged: unwanted material into lung causing inflammation or infection
Microbiologic insult
- Aliquot of organisms; dentition and presence of gingival disease
- Virulence of organism e.g. influenza
- microaspirations, (how variable were the organisms and how many organisms were there)
- number of organisms influenced by what type of disease (gum/bad dentition = anarobes and microphilic organisms = more likely to get LRT infection after microaspirations)
Particles
- Microorganisms
- “dust”; PM10(air pollution)
- Allergens: pollen (large, pine pollen cause cause hay-fever(nose) not asthma(airways))
- Therapeutic (deposit particles in airways. narrow size distribution)
1. Droplets (wet nebulisers)
2. Suspensions(inhalers); pMDI
3. Dry powder
4. Specialised; Pulmospheres (engineered nanoparticles. liposomes(fat droplets w. drug inside))
Deposition of particles in the lung By impaction and Sedimentation
URT infection protection related to impaction on airway surface removed by mucociliary escalator (where depends on size) a) Physical Defense Mechanisms Nose= particles >10u (humidfy + removal of particulates.) -Turbanents a) large SA b) generate turbanent flow inspired air has to do 90degree turn to enter lungs, impact oropharynx airways= particles 5-10u 1. Upper airway filtering 2. Reflexes - cough and sneeze 3. Mucociliary escalator b) Cellular Defense Mechanisms Alveolar: Particles
Other factors other than particle size
size
absorb water?
electrostatic charge
Muco-ciliary clearance
Mucus layer + cilia + epithelial cell mucociliary escalatory cilia are on epithelial cells cilia beat within the peri-ciliary fluid interact with overlying mucus layer
Ciliary Function
- Ciliated cells to 17th generation of airways
- > 200 cilia per epithelial cell
- Effective (move mucus layer forward) and recovery (peri-ciliary fluid) stroke
- Continuous and coordinated ciliary action: via intracellular signalling
- Mucus and sol
- Role in “chemo-sensing” the microenvironment: includes Sonic-Hedgehog
Cilia structure
2x central tubules
9x pairs of outer tubules
linked by diniane arms
Ciliary (Dys-)Function
-Congenital (Chronic resp. disease due to absence of diniane arms. structure)
-Acquired (more likely)
a)-Structure
b)-Function; ciliary beat frequency, coordination
-bacterial toxins
-inflammatory mediators
-chemical/gaseous stimulants
(ciliary dysfunction= secretions from airways arent cleared= secretions become infected= create more inflammation and more mucus.)
-vicious cycle of infection, inflammation and airway damage
Mucus Components
H2O and ions Glycoproteins (mucins – 14 genes) Proteoglycans Lipids Other proteins eg lysozyme, defensins (DNA)
Mucus
Sources include goblet cells (stain pinky purple) and mucus glands (deliver via ducts)
-down to 17th generation
Discontinuous layer in periphery, continuous and thicker centrally.
-total cross sectional area of small peripheral airways is enormous (hyperplasia/discontinuous required) vs small central (hypertrophycontinuous required)
Roles of Airway Mucus
- Protects Underlying Epithelium
-Physical barrier
-Dilutes chemicals ( oxidants & proteases)
-Absorbs gases - Traps particles (dust or bacteria) and facilitates removal (mucociliary escalator)
- Provides environment for luminal cells (water/electrolyte fluxes) (binds
water and hydrates) - (mucus + peri-ciliary fluids) Contains anti-microbial substances eg CAPs such as defensin
Peri-ciliary Fluid/ Airway Surface Lining Fluid
- Volume critical for ciliary function (inadequate in CT. mucus sits right on cilia and cilia cant beat)
- May modify mucus layer (hydrates mucus)
- Sources include Clara cells, epithelial cells (largely)
- Regulated by active ion transport
- Amenable to pharmacologic modulation
Ion and Water Transport across the Airway Epithelial cell
Na transcellularily Cl- para cellularily Na+/K+ pump in base Enaga Na+ channel in airway surface Cl channels cAMP required to drive Cl channel -7 repeating intramembrane components -cytoplasmic components where cAMP binds CT gene codes for Cl 3 genes + transports bicarbonate
Correction of Ion and Water Transport
- Gene Transfer
- Stabilisers
- Potentiators e.g. ivacaftor (opens Cl channel in CF for cure)
- Correctors e.g. Vx 809
- ENaC inhibitors
Normal Lung Defense in disease
-mucus contains a few neutrophils normally
Inflammation= increased volume. different mucin types (different physical properties; sticky)
1. Increased ^ viscosity
2. Increased ^ secretion
3. Increased ^ solid content; DNA (infection, break down of neutrophils, release of DNA) (recombinant DNA clinically used to alter mucus physical prop in disease)
4. Decreased PCL (peri-ciliary fluid. osmotically active substances via inhalation. natural sugars/manatol)
5. Decreased ciliary function
6. Decreased cilial beat frequency structural damage
Cough
Removal of material from LRT
(close glottis. forcibly expire using abd. muscles. increase to high pressure in thorax. open glottis)
Requires:
-Development of high intra-thoracic pressure
-Sudden release of pressure
-Generation of high linear airflow velocity
-(Excess) mucus and trapped material removed by sheer forces (assoc. with rapid flow of air)
-ability of airways collapsing appropriately, to generate high linear velocity of air (bronchiecticis = damaged + dilated airways = abnormal cough)
Only effective to 16th generation of airway (linear velocity of airflow too low in small airways (large total cross sectional area))
Normally doesn’t clear normal airway mucus – layer too thin
Greater volume or more viscous mucus builds up to thicker layer which is removed by sheer forces
Defence Mechanisms in the Lung Periphery
No muco-ciliary escalator No effective cough mechanism (i) Alveolar macrophage (cellular) -Resident phagocyte (major source of IL8, drags neutrophils marginalised in pulmonary capillary into alveoli) -Antigen-processing cell -Immuno-regulation (ii) PMN leucocytes (cellular) -Recruited phagocytes (iii) Immunoglobulins (+ antibacterial peptides) (humoral)
Requirements of a cough
- Development of high intra-thoracic pressure
- Sudden release of pressure
- Generation of high linear airflow velocity
- (Excess) mucus and trapped material removed by sheer forces (assoc. with rapid flow of air)
- ability of airways collapsing appropriately, to generate high linear velocity of air (bronchiecticis = damaged + dilated airways = abnormal cough)
Neutrophil location
1/2 in pulmonary blood vessels/capillary lining
1/2 circulating
-present so can be recruited into lung + fight infection
Lymphoid tissue location
right in periphery of lung
assoc. with airways
(equivilant of Peyers Patches in gut) lung outpouching of gut
Alveolar Macrophage location
interstitium or alveolus
Immune response in lung to Microbiological insult
- Bacteria multiply in alveolus
as the alveolar macrophage migrates to the site of infection (produces IL8 then conducts immunological conduction) - Neutrophils migrate (IL8 chemotaxis) towards the infection and the capillaries start to leak exudate into the interstitium
Pneumonia + Lung consolidation
-alveolar walls are thick and red as are congested with RBC
-alveoli full with bacteria, neutrophils and cellular debris
-neutrophils filling alveoli rather than air causing shadowing in chest-radiograph
Shadowing of Chest-Radiograph
Filling of alveoli by neutrophils
rather than air
Penumonia Macroscopic effect/Red Hepatization stage of Pneumonia
Red Hepatization
-no air
-now chock filled with neutrophils
-red= capillary congestion
=all the inflammatory mediators are generating the increased blood flow
-next stage= hypoxic vasoconstriction (pulmonary vessels very sensitive to hypoxemia. constriction. wont see RBC in alveolar wall. lung solid but grey (reduced blood flow to reduce diffusion maintain Vpmax)
Scenario: Predisposition to Pneumonia
-Virulent organism
-Poor dental hygiene
-Impaired swallowing (Dementia maybe due to multiple small strokes effecting her brainstem, impaired swall
-Impaired glottis
- Cilial structure and function (Previous infection, Smoking (toxins effect freq + co-ord)
-Mucus (Previous infection, Smoking (increased number g.c. and larger glands); “chronic bronchitis”)
-Impaired cough ( Muscle weakness (non-forceful cough) ; deconditioned (/malnourished), Impaired glottic closure – vocal cord palsy, Abnormal airways, Abnormal mucus)
-Impaired innate immunity (age) (drugs, corticosteriods for joints, reduces cellular immune survalance)
-Immunologic effects of (Co-morbidities (heart failure predisposes to lung infection), Therapies (influence cellular and humoral function)
(Impaired cellular function, Neutrophils – bacteria, fungi, Lymphocytes – bacteria, protozoan)
Cigarrete smoking effect on lung
hyperplasia (increased number) of goblet cells
hypertrophy of mucus glands
=increased mucus production
=requires more effective mucociliary clearance
Other issues with patient
Treatment decisions -capacity (to make decisions) -advanced care directives -ethical considerations (re management) Antibiotic choice/route/duration Significance of pleural effusion -investigation -management
