5. Pulmonary Host Defense Flashcards
Integrated Pulmonary Defenses
- Mechanical protection
a. ____ - ____, glottis, ____
b. ____ - ____, mucous, ____, - Innate immune mechanisms
a. ____ - ____, collectins, ____
b. ____ - respiratory ____, phagocytes - Adaptive immunity
a. ____ (CD4, CD8 T cell)
b. ____ (antibody - B cells)
There are 3 levels of host defense for the respiratory tract(We think of T cells and B cells when we say host defense but for Respiratory tract, yeah it’s important but the first level of defense is 1. MECHANICAL PROTECTION
upper airway turbulence cough lower airway branching cilia
soluble complement defensins cellular epithelium
cellular immunity
humoral immunity
Integrated Pulmonary Defenses (cont.)
Within the mech protection we have the Upper airway and the Lower airway. This is responsible for the overwhelming defense of the ____. Only if this is breached, do you then call in to play the 2. ____ immune mechanism of the respiratory tract
Only if you breach Mechanical protection and only if overwhelm Innate immune mechanisms, is ____ Immunity called into play (called in to play via cellular immunity and humoral immunity
respiratory tract
innate
adaptive
Mechanical protection - the upper airway
- Nares & hypopharynx:
• ____ create turbulence which causes particulate material
to settle onto surfaces
• Nasal hairs - ____
• Rhinorrhea - ____ & sneezing
• Highly effective for particles ≥ ____ uM - Epiglotis/glottis:
• ____
• ____
• ____ - Respiratory mucus:
• Impedes bacterial ____
nasal turbinates
filtration
cellular desquamation
10
swallowing
gag
cough
adherence
Mechanical protection - the upper airway (cont.)
- Nasal turbinates are structured to create turbulence in the upper respiratory tract which causes particulate material to settle onto surfaces. The main point of the turbinates are to create ____; and to ____ the air as it is inspired into the Lower resp tract
- Nasal hairs are covered with mucous filters
- Rhinorrhea causes desquamation and sneezing
- Proximal to more distal mechanical defense is size specific. - In a hospital setting, defects here in the ____ are responsible for the majority of hospital acquired pneumonia (And even community acquired lower resp tract infections bc if you breach these, the lower defense mechs not going to have capacity to respond)
- V important function: globs up particulate matter. Its part of the ____.
In the Upper resp tract it is how body gets rid of organisms. Just like most infections, inoculum is critical. So getting rid of inoculum through these mech barriers is critical for defense of the ____
turbulent airflow warm upper resp defense mucociliary ladders lower resp tract
1.a. Mechanical protection - the upper airway
Defects of the upper airway with loss of mechanical protection:
Altered consciousness
• Drug ____, anesthesia, CNS events
Laryngeal dysfunction
• Bulbar dysfunction – ____ & neuromuscular diseases
• ____ procedures
Endotracheal tube or tracheostomy
• Major risk factor for pneumonia – ____
Oropharyngeal flora & respiratory mucosa adhesive properties
• Increased ____ flora with extensive dental disease (loss of anaerobic flora in patient without teeth)
• Within a week of illness & hospitalization, normal respiratory flora is replaced with gram negative bacteria (____)
overdose myesthenia gravis oro-pharyngeal surgical ventilator-associated pneumonia anaerobic opportunistic
1a. Mechanical protection - the upper airway
Defects that lead to Upper Resp mechanical defense being lost. (Upper respiratory= oral pharyngeal cavity) This is where your Dental field (oral pharyngeal cavity) and the lower resp tract interact/intersect.
- Also ____, coma. These are the most common causes of ____ infections.
- Neuromuscular diseases include stroke having defective ____ functions, because loss of coordinated activity. Upper resp tract, epiglottis and cough reflex is critical. During surgical procedures, if you lean a PT back, PT might aspirate something you might not what them to aspirate.
- If you put a ventilator, you are basically bypassing the ____ so now you have a risk for LRT infections
- He introduced Resp tract mucous before and it has a lot of functions; one of which is acting as a ____ - flowing out microbes, also binds microbes. When people are sick the mucous adhesive properties change and the flora that colonizes the URT changes. Healthy people mostly have ____, they get colonized by gram neg bacteria when they are ill, and that changes the type of bacteria that can enter the ____.
Within a few weeks of illness/hospitalization, the flora of URT changes due to changes in adhesive properties of the ____ That totally changes the types of infections that people who are sick are susceptible to.
Most the anaerobes colonize the gingival crevices of your teeth, it’s a growing field of study the microbiome of the oral cavity
strokes LRT swallowing upper resp defense mechanism ladder anaerobes LRT mucous
Case example 1:
Defective mechanical defense - upper airway
DH - 63 year old man with poor dentiton and history of heavy alcohol use presents to ED with fever, chest pain, cough, foul-smelling sputum
Two kinds of infections:
1) opportunistic - agent is not pathogenic unless there is a defect in ____.
Ex ____ is a opportunistic infection.
2) ____, organisms that have virulent factors that make them able to create infections
in normal hosts. Ex. ____ is virulent.
Interpreting xrays: white is tissue, bone, fluid. Black is air.
Is pointing to abscess in lung.
The mans stats are listed, he has foul smelling sputum, what causes this? ____.
host immune system pneumocytis pneumonia virulent tuberculosis anaerobes
Case example 1:
Defective mechanical defense - upper airway
Lung abscess due to aspiration of ____ caused by loss of consciousness with decreased gag / cough.
Usually mixed flora - including mouth anaerobes (foul smell) if teeth are ____.
Loss of consciousness when he drank too much and blacked out ; he aspirates the oral flora and the saliva he aspirated is full of anaerobes
“If teeth are present” – Usually people who don’t have teeth don’t get ____ because they don’t have gingival crevices
anaerobic oral flora
anaerobic abscesses
Case example 2:
Defective mechanical defense - upper airway
Ventilator-associated pneumonia (VAP) due to ____ or ____ bypass of ____ protection
VAP occurs in up to 30% of intubated patients and causes 40,000 to 70,000 deaths in the US each year
A third of the people with ventilators get VAP, its bad because they are already respiratory compromised You get VAP because you have entrance of bacteria directly bypassing the URT (____).
endotracheal tube
tracheostomy
upper airway
mechanical defense
1.b. Mechanical protection: the lower (conducting) airways
Bronchial Branching
• 20 orders of bronchial branching from trachea to alveolar ducts
• Increased____ lead to decreased ____, and increased ____ with mucosal surface
• Effective for particles ____ uM
Mucous
• Lower ____ layer
• Mucinous layer (____)
Cilia
• 200 per cell at 12 - 15 beats per second
• Propel particulates & mucoid layer up
Mechanical protection and muco-cilliary ladder require coordination with the ____.
total CSA
forward velocity
contact
5-10
sol (liquid)
proteoglycans
cough reflex
- b. mechanical protection: the lower (conducting airways)
- Cross-sectional area becomes exponentially ____. If you breath in a certain amount of air per min, and your cross sectional area as that air moves towards the distal lung gets greater and greater, the forward velocity will ____. Particulates that are suspended in gas are more likely to hit ____ or settle.
-Branching works in concert with the mucociliary function Airways lined with mucous which has two
layers
-lower sol in contact with ____ and interacts w/ cilia. & floating on top of the lower sol layer we have ____ layer - v good at binding microorganisms
- Respiratory epithelia are lined by cilia, they have rhythmic beating. When cilia beats, it is able to push the mucous layer bc it has this nice watery lower sol layer, able to push mucous layer up - gets coughed and expectorated
- Muco-cilliary ladder = ____ layer on the cilia. You need proper ____. This is why with neurological defects one is at risk for resp infections. (They not only have compromised ____ function but also when things come up they cannot ____ it out)
greater decrease resp epithelium mucinous mucinous cough reflex gag swallow cough
Case Example 3:
Defective mechanical defense – conducting airways:
AB - 19 year old man presented with fever, shortness of breath, green sputum for 7 days
Sputum gram stain: Gram positive ____ in ____
Sputum grew ____ and he was treated with cefazolin.
He improved and on discharge was instructed to find a primary care doctor.
Over the next 12 years he had multiple episodes of bronchitis including several with fever, sputum and shortness of breath. Each time he was empirically treated at a clinic with antibiotics.
Since the last episode 6 months ago, he has not regained his exercise capacity, his sputum production has persisted, and recently become ____ and occasionally ____.
Side note: Classic tuberculosis is a ____ disease.
Tuberculosis More likely to reactive in the upper lung
The 19 yo PT’s gram stain: Gram positive cocci - ____
Reads the history. He never fully got better
cocci
clusters
staph aureus
green
blood-flecked
upper lobe
staph aureus
Genetic testing - F508 / ∆I507 genotype in the CFTR gene
Abnormal pattern in both lungs. Not like before where we saw a solid area of infiltrate.
He now has cystic things.
This is a ____ bronchi = ____.
Gram negative ____ – ____. Its rare, you don’t just get it as an outpatient. So then he got tested (genetic tested) for this ____ mutation. ____ that controls flow of water across the resp epithelial cells; if it is mutated it doesnt properly transport water and mucous is ____. ____ doesnt work.
large/dilated
bronchiectasis
rod pseudomonas cystic fibrosis ion channel thick mucociliary ladder
Cystic Fibrosis - defective mechanical lower airway defense (as well as innate immune defense)
Mechanical defense:
•Defective respiratory epithelial water transport leads to ineffective ____
•Bronchial distortion with loss of airway ____
Innate defense:
•Lack of antimicrobial peptide activity (defensins) due to
____ defect
Consequence:
•Chronic airway colonization & ____ infections
•Bronchial damage (____), airway obstruction
•Self perpetuating ____ of infection and further damage
CF - defective mechanical defense of the ____
Epithelial water transport is screwed up ; the ____ layer is messed up for the mucous, it does not transport up- its too viscous and thick.
That then leads to damage to bronchial airway (loss of branching, gets big/dilated) - and you dont get the normal filtering out of particles
____ in the lower airway;
Water defect in the mucous leads to an ____ defect And these antimicrobial peptides don’t work either
Chronic airway colonization and recurrent infections leading to persistent ____. Airway obstruction because you get big dilated bronchi and things don’t clear.
mucocilliary
branching
osmotic
recurrent
bronchiectasis
cycle
lower airway
sol
defensins
osmotic
inflammation
Case Example 4:
Defective mechanical defense – conducting airways
68 year old man with whooping cough as a child (pertussis) and several episodes of LLL pneumonia
Bronchiectasis (focal)
Bronchiectasis - only in one area so its called ____ bronchiectasis
So you can have a genetic defect like CF that leads to ____ or you can get ____ like seen here with this Case.
What causes focal Bronchiectasis? ____ cough used to be #1 cause of it. ____ can cause this. Even just bad ____ can cause it.
Focal Bronchiectasis is another example of conducting airway system ____ defect
focal
diffuse
focal bronchiectasis
whooping
TB
pneumonia
mechanical
Case Example 5:
Defective mechanical defense – conducting airways:
Former heavy smoker with incomplete resolution of infiltrate following his 2nd recent episode of left-sided pneumonia
Post-obstructive pneumonia due to ____
bronchogenic carcinoma
Case Example:
Defective mechanical defense – conducting airways:
Aspirated foreign body
You have post obstructive pneumonia - whole ____ filled with infiltrate
Pneumonia due to aspirated dental prosthesis
right lower lobe
Case Example 6:
Defective mechanical defense – conducting airways: Non-draining bulla or cavity
35 year old man - treated for TB about 5 years ago, now with hemoptysis for the past year. Re-treated for TB (despite negative sputum AFB) with no improvement.
____:
Blob of fungus
fungal colonization within an old cavity
Due to defect of conducting airway, this is not ____, so it allows establishment of a aspergilloma
Causes ____, doesnt usually cause ____ infection although it can.
asperigilloma
draining
hemoptysis
systemic
- Innate immunity in the lung
Cellular
• Phagocytes
• ____ are the primary immune defense system in the lung (≥85%)
• ____ (PMN) are rare in lung (≤5%) but recruited in response to stimuli
• ____ - direct killing
- Respiratory ____ cells secrete soluble products
- ____ peptides
- mediators to recruit ____
Soluble
• ____ - aggregate, opsonize
• ____ - direct lysis, opsonize
• ____ - direct lysis
- not every innate immune cell is a specialized professional immune cell
- most cells (esp. epi cells) have ____. respiratory epithelial cells have their own innate immune system
Upper Conducting airway is critical
Mechanical defense is critical
Now, lets talk about innate immunity in the lung, which is only called in to play only if the upper ____ barriers are breached.
It can be broken down into 1) cellular factors and 2) soluble factors
Innate immune functions are generalized throughout the body but there are some specific components that are uniquely specialized to the ____.
macrophages neutrophils NK cells epithelial direct antimicrobial immune cells
surfactant (collectins)
complement
defensins
innate immune function
mech
respiratory tract
2.a. cellular innate immunity
How do cells recognize as foreign something never encountered before?
Pattern Recognition Receptors :
Toll-like receptors - bind to conserved ____ components:
• ____, flagellin, ____, peptidoglycan, etc
• Nucleic acids not in mammalian genomes - ____, ____
• In the lung: ____, respiratory epithelial cells
Lectins - surface receptors recognize ____ patterns
• In the lung: ____r
Opsonization - soluble pattern-recognition binding proteins that coat microbes
• target them for ____ & trigger immune cell activation
• In the lung: ____, complement,
Adaptive - responding to something it has seen before ,
But Innate - responds to something recognized as ____ (via things like Pattern Recognition receptors)
Macrophage mannose receptor is a lectin that is well studied in the lung.
Bacterial Carbohydrates is very different from Carbohydrates of ____
Opsonization - Soluble factors may have direct effects that are ____ or may serve as ____ in order to direct phagocytes to foreign microbes In the lung: we have collectins - ____ specific multifunctional proteins
We have complements ____ (broadly distributed opsonin)
microbial LPS (endotoxin) lipoproteins dsRNA unmethylated DNA macrophages
microbial carbohydrate
macrophage mannose receptor
phagocytosis
colelctins (surfactant)
foreign
mammals
antimicrobial
opsonins
lung
everywhere
It is not only specialized immune cells that participate in innate immunity
Immune activity of airway epithelial cells:
Input:
Pattern recognition receptors involved in recognition of ____ by airway epithelial cells
Output:
Secretory products of respiratory epithelial cells active in ____ defense
Immunity is not just carried out by immune cells, its carried out by almost every cell.
In the lung, the airway epithelial cells are critical.
The input, the afferent component, is carried out by all these ____ (points to chart).
The output is that respiratory epithelial cells in response to appropriate cells puts out ____, ____ mediators to attract inflammatory cells and antimicrobial peptides.
There is crosstalk between ____ functions, the chemotactic and inflammatory mediators increase innate immune cells but also call in ____ immune cells.
microorganism innate TLRs inflammatory chemotactic innate and adaptive adaptive
a. Defects of cellular innate immunity
____ - chemotherapy, leukemia, bone marrow transplant
• Invasive ____ disease, rapid ____ infection
• ____ and ____ in the bone marrow transplant or chemotherapy patient
Desquamated & injured respiratory epithelium
• ____ / smoke inhalation
• Post-____
• Increased susceptibility to ____ (S. pneumonia, Staphylococcus)
Now we will talk about the specialized immune cells. ____ is one of the most common causes of lung infections that we see, just because neutropenia is common. Neutrophils rapidly turn over cells, derived from the bone marrow, and most chemotherapy agents hit the white cell/ neutrophil lineage hardest, (chemotherapy also hits other cells (red cells/ and platelets but they can be transfused), and endogenously in bone marrow transplant and leukemia also results in loss of neutrophils.
Consequence of neutropenia occurs with ____ disease (that you would not see in immunocompetent host, such as gram neg pneumonia, invasive aspergillosis) or rapidly ____ infection.
Direct injury to epithelium can occur from airway burns or smoke inhalation. People with influenza actually die from ____. Many ____ infections enhance sensitivity to bacterial pneumonias.
neutropenia fungal progressive bacterial gram negative pneumonia invasive aspergillosis
airway burns
influenza
bacterial pneumonia
neutropenia fungal disease progressive bacterial post viral bacterial super infections viral
2.b. Pulmonary Innate Defense: Soluble antimicrobial proteins (large proteins)
Collectins – Specialized ____ system (multi-functional)
____ proteins - SP-A & SP-D (not just for lung physiology!) ____ (MBL)
Aggregate, opsonize, fix ____
Complement (C3a, C5a, Properdin B)
____
chemotaxis
____
Others with direct antimicrobial activity:
____
Lysozyme
____
respiratory system
surfactant
soluble mannose-binding lectin
complement
direct lysis
opsonize
lactoferrin
transferrin
2.b. pulmonary innate defense: soluble antimicrobial proteins (large proteins) (cont.)
Other proteins he will not talk about but are multifunctional proteins with antimicrobial activity He wants to mention the collectins that are a group of specialized respiratory system proteins that have antimicrobial ____ immune functions, they aggregate organisms, opsonize them and fix complement triggering the alternative pathway. The collectins have a typical structure with a ____, that binds carbohydrates of microorganisms, a ____, and another region that does the ____.
Some can aggregate together in large groups that are effective in aggregating microorganisms. There are some that are specific microbial, ____, and others with ____activity (ex blowing up a balloon is easier when its big because the surface tension is greater when its small) so if the lung is a balloon you wont be able to start inspiration without surfactant that line alveoli, that help decrease surface tension, and start out to be thick and end up being thin once the lungs are blown up, allowing the lungs to expire based on elastic recoil.
There are also secondary functions, binding ____. Overall multifunctional.
innate
lectin domain
long linker region
action
mannose-binding lectins
surfactant
microorganisms
