Lecture 15- Lung defence mechanisms Flashcards
Lung Defence Mechanisms
-Need to preserve ‘sterile environment
-Lungs have “direct” communication with the external environment, so exposed to numerous potential “insults”
With our high ventilation rate, particularly during exertion, we are intaking huge amounts of air
Why do lung transplants often fail
With our high ventilation rate, particularly during exertion, we are intaking huge amounts of air all of which contains the potential insults.
This could be why lung transplants have particularly high rejection rates
Microbiome
totality of microbes,; bacteria, fungi
We know about these from now technology
Healthy MB: protects against disease
Altered MB in diseases> inflammation > disease.
Lower respiratory tract is sterile/non-sterile?
Not sterile, has a healthy microbiome for protection. Altered in disease, which leads to disease
There is ‘cross-talk’ between the lung and gut microbiome (think of embryological origin!)
What can we/can;t we do to our microbiome?
CAN: alter/treat with antibiotics
CANNOT: restore to normal
Upper Airway Defence Mechanism
- Effective coordinated swallowing mechanism
- Protection of lower airways by epiglottis and glottis
- cough
- sneeze
Upper Airway Microbiological insult
Micro-aspirations occur often (especially with drinking) the effect of these depend on;
- Aliquot of organisms (dentition and gingival disease)
- Virulence of organism (flu)
URT protection from particles
Impaction of particles on the airways, which is then removed by the mucociliary escalator. Where they impact and are removed depends on SIZE
Biggest (>10m): Nose and pharynx (large SA, turbinates, right angle turn)
Medium (
Types of particles
Micro-organisms
‘Dust’; PM10
Allergens; pollen
Therapeutic use of knowing particle size?
Allows us to deposit particles in specific airway locations
- Droplets
- Suspensions (asthma)
- Dry Powder
- Specialised; pulmospheres
How are the particles actually cleared?
Muco-ciliary Escalator
Mucus layer that catches particles, serous paraciliary fluid layer that cilia move in.
Cilia’s effect and recover stroke is continuous and co-ordinated via intracellular signalling.
There are ciliated epithelial cells to the 17th generation of branching.
Role in ‘chemo-sensing the microenvironment.
Cilia Structure
2x central micro-tubules
9x outer microtubule doublets
Linked via dynein arms
Cilia (Dys)function
Can be
Congenital: affect structure
Acquired (more likely): impact both structure AND function (don’t beat as fast or are unco-ordinated)
toxins released from bacteria etc
Quickly leads to a viscous cycle of infection, inflammation > disease
Mucus. Made out of and sources?
- ***Glycoproteins (mucins-14 genes)
- H20 and ions
- Proteoglycans
- Lipids
- Other Proteins (eg: lysozyme, CAPs)
Sources: Mucus glands & Goblet Cells (to 17th gen)
What is the distribution of the mucus?
Discontinuous layer in periphery, continuous and thicker centrally.
This is to work directly at larger airways.
Roles of Airway Mucus
1) Protect underlying epithelium
- physical barrier
- dilutes chemicals
- absorbs gases
2) Traps particles and facilitates removal
3) Provides environment for luminal cells (binds water and hydrates)
4) Contains anti-microbial substances eg) CAPs such as defensin
Peri-ciliary Fluid
Cilia beat in this, but the VOLUME is critical (think CF)
- May modify mucus layer
- Regulated by ‘active ion transport’
- Amenable to pharmacologic modification
Source: Club cells
Ion & water channels in Airway Epithelial cell
Normal transport of NaCl, water and bicarbonate require:
N+/K+ pump in base
Sodium and Cl- channels in apical membrane
In CF there is no Chloride channel
Correction of Ion and Water Transport
- Gene transfer
- Stabilisers
- Potentiators eg) ivacaftor
- Correctors
- ENaC Inhibitors
How do we get a compromised Muco-ciliary clearance in Disease? (asthma, COPD, bronchictisis)
Increased:
viscosity
secretion
solid content (DNA)
Decreased:
PCL
ciliary function
cilia beat frequency
Structural damage occurs
Cough
-Removes material from LRT
> Block glottis, using thoracic and abdominal muscle develop high intra-thoracic pressure. Open glottis > sudden release of pressure at an extremely high linear airflow velocity.
Excess Mucus (thicker or more viscous) & trapped material are removed by sheer forces. Normal airway mucus not usually removed, as it's too thin.
Only effective to 16th generation of airways (linear velocity of airflow too low in small airways)
Defence in Lung Periphery
NO mucociliary escalator or effective cough mechanism
1) Alveolar Macrophage
- Resident phagocyte
- APC
- immuno-regulation (drag neutrophils to site)
2) PMN leucocytes
- recruited phagocytes
3) Immunoglobulins
Alveolar macrophage
Sits in either intistitium or alveolar itself, Invades 1st, conducts inflammatory/immunological response, releases IL8 which drags neutrophils into alveolar space to site of insult
In pneumonia the alveolar…
Alveolar aren’t filled with air, but chock full of neutrophils and bacteria
‘Red Hepatization’
