Respiratory Block Flashcards
Where are mast cells found?
Found everywhere but mostly on sites exposed to the external environment. Also very common to be found near blood vessels, nerves and glands.
What are some external stimuli that can activate the mast cell?
Drugs such as morphine and vancomycin (red man syndrome). Mechanical, UV light/heat, Allergen (IgE), stings and osmotic stimuli causing hypertonic saline (exercise induced asthma).
What are some internal stimuli that can activate mast cells?
Activated complement and neuropeptides
Explain the allergen-induced mast cell degranulation process.
Antigen-specific IgE must be produced by initial exposure to allergen. IgE is typically produced in atopic subjects which is heritable.
Once IgE antigen specific is formed it will cross-link to the FceR1 that can be further activated by antigen binding.
What does it mean to be an atopic patient?
Means they have the atopic triad - asthma, hay fever, eczema.
How do we think desensitisation develops against allergens?
Exposure to the allergens stimulate Treg cells to form which oppose auto-immunity and suppresses Th2 development.
What are the characteristics of FceR1?
It has no intrinsic kinase activity so it has ITAMs (immuno receptor tyrosine-based Activation Motifs) that act as a scaffold for other kinases to become activated.
What is the pathway of FceR1 activation by allergen binding?
Allergen binds to the receptor, which phosphorylates itself. Syk is recruited which is a tyrosine kinase that brings in Lyn. The Lyn phosphorylates the FceR1 itself. They both activate other tyrosine kinases. Eventually leading to PLC (phospholipase C) activation.
DAG (PKC) and IP3(Ca2+ mobilisation) leading to eventual degranulation.
What are the outcomes of FceR1 activation? Specifically MAPK and PLC produced.
Activation of MAPK and PLC will cause degranulation to occur, Arachidonic Acid (AA) mobilisation, cytokine gene transcription.
MAPK is only involved in AA mobilisation and cytokine gene transcription.
Is mast cell degranulation cytotoxic?
No
What are the three different stages of mast cell communication with the internal environment?
Immediate (preformed granule) - histamine, TNF-alpha, heparin and tryptase (30-45 seconds)
Rapid (Peaks 10-30minutes) - Cys-LTs and PGD2
Slow (Hours to days) - IL-4 (promote IgE), IL-5 (recruits eosinophils) and GM-CSF (promote eosinophil life and macrophage activation) that enforce the Th2 phenotype. Essential activation of cytokine genes for Th2.
What is the response to the immediately released mediators (Histamine on H1 receptors)?
Bronchospasm, Pain, Itch, mucus secretion, vasodilation (hypotension), increased vascular leak (permeability). These usually involve the H1 receptors.
It can also act elsewhere to increase gastric secretion (H2 receptors), increased wakefulness (CNS) and positive chronotropic and ionotropic (H2).
What is the outcome of delayed release of mast cells (cys-Leukotrienes)?
LTA4 is the precursor to LTC4. LTC4 form LTD4, LTE4 that act on CysLT1 receptors.
No known physiological roles other than inflammation (good target).
Causes hypotension in anaphylactic shock due to vasodilation and decreased CO.
Causes mucus, oedema and ASM (airway smooth muscle) shortening - asthma.
Oedema and mucus found in hayfever caused by this.
Where are Cys-Leukotrienes produced and their stimuli for release?
Eosinophils, mast cells and macrophages (inflammatory cells only).
Stimulated by allergens, C5a and platelet activating factor. Increase in cystolic calcium produced in infection, allergic reactions and other forms of inflammation.
What is the overall response from activating Cys-Leukotriene receptors? What about LTB4 specifically?
Bronchoconstriction, vasoactive and leak vessels (tissue oedema).
LTB4 involves promoting inflammation by attracting leukocytes. Does not act on the smooth muscles.
What are the site of drug actions along the AA pathway?
Glucocorticoid steroids (PLA2), Aspirin (COX), Coxibs (COX-2) and Montelukast (Cys LT receptor antagonists).
The Cys-LT receptors prevent mucus production and bronchoconstriction.
What is the response of delayed and protracted release of cytokines from the mast cell?
This response is prolonged in cytokines - IL, TNF, CSF and chemokines.
Usually comes on slow and induces gene expression changes (proinflammatory cell infiltration) leading to inflammatory cell infiltration.
What are some endogenous and pharmocological inhibitors of mast cell activation (specifically disodium cromoglycate)?
Endogenous: PGE2,adrenalin and cortisol.
Pharmacological: Disodium cromoglycate (reduces mast cell degranulation in some patients as well as eosinophil activation). It also stimulates annexin-1 release that resolves inflammation.
Genereally used for allergic responses of mucosal surfaces (not orally active)
How does omalizumab work to inhibit mast cell activation?
It is a humanised antibody to IgE. Prevents the IgE from cross-linking to FceR1 so mast cells are unarmed.
How are the use of aspirin and selective COX-2 inhibitors for asthma and anti-allergic agents?
Mixed roles of prostaglandins in allergies. No real benefits in asthma or hayfever. Sometimes aspirin can provoke asthmatic symptoms (but aspirin induced asthma can be treated with LTRA (leukotriene receptor antagonists)).
Blocking COX leads to increased Leukotriene production.
Are H1 receptor antagonists useful in colds or asthma?
Not useful - only to some extent.
What are the three classes of H1 competitive antagonists and their adverse effects and example?
Sedative - promethazine (sedative)
Non-sedative - Terfinadine (sudden ventricular arrhythmia)
Newer non-sedative - Loratidine (reduced risk of unwanted cardiac effects)
How many classes of hypersensitivity reactions are there and what do they generally involve?
Type I - IgE, mast cell and lipid mediators
Type II - IgG and IgM against cell bound or ECM antigen
Type III - IgM and IgG immune complex deposition
Delayed Type Hypersensitivity IV - CD4 mediated
What does Type I hypersensitivity involve and what does it cause?
Usually causes allergy through immune-mediated inflammation to harmless environmental antigens.
Found in atopic individual who have: High IgE levels, large numbers of eosinophils and large numbers of IL-4 secreting Th2 cells.
What are the general steps to Type I hypersensitivity after IgE mediated inflammatory response to antigens?
Sensitisation phase which is followed by;
Response phase: local (common) or systemic (rare). Locally it will cause rhinitis, bronchoconstriction and conjuctivitis. Systemically will cause anaphylaxis.
Responses have both immediate and late phase.
What contributes to the effector (allergic) mechanism?
Allergens, Th2 cells, IgE, FceR1, mast cells and eosinophils
What are the typical allergens and their characteristics that elicit Type I hypersensitivity?
Pollen, house dust mite, food, etc.
Should have repeated exposure, highly soluble (to pass through mucus), very stable and hard to degrade and introduced in low doses.
What is the mechanism of sensitisation in Type I hypersensitivity?
Low dose Antigen enters the mucosal route. It is taken up by APC and displayed to naive T cells. The APC produce IL-33 that indirectly releases IL-4 when stimulating the T-cell. This leads it to differentiate to Th2 cells (increasing in IL-4, IL-5 and IL-13)
Upon re-exposure the Th2 already present will promote IgE secretion proliferation and isotype switching.
How does the Th2 differentiation work during the sensitisation phase?
The DC’s do not actually produce IL-4 to co-stimulate the naive T-cell. DCs produce IL-33 which activate basophils to directly secrete IL-4 onto the naive T-cell. This aids the differentiation to Th2 and productiong of IgE.
Why are basophils key for the initiation of allergen specific Th2 responses?
They can act as APC (express MHC I and II, PRR) and importantly secretes IL-4.
Why does Th2 differentiation lead to IgE isotype switching?
The activated Th2 cells can stimulate B-cells to isotype switch to IgE.
What is the response phase of Type I hypersensitivity?
Found in mucosal and epithelial tissue near blood vessels. Mast cells contain pre-formed granules, binds IgE to FceR1 and surface bound IgE is very stable.
Once allergen is bound it will result in granular exocytosis and the synthesis of lipid mediators, cytokines and chemokines.
What is the immediate phase after mast cell activation - wheal and flare?
Occur in seconds due to pre-formed granules that are rapidly metabolised.
It causes blood vessels to dilate and leak plasma. Localised swelling around the site of challenge (wheal). The blood vessels dilate further and engorge with blood (flare)
What is the late phase after mast cell activation?
Induced mediators released such as chemokines, cytokines and leukotrienes.
Involves cell infiltration and prolonged oedema and may/or may not cause smooth muscle contractions.
What are the different types of allergic reactions depending on where it occurs?
GI tract - Diarrhoea vomiting
Skin - swelling itching urticara
Airways - nasal blockage, coughing, phlegm and asthma
Blood vessels - increase tissue fluid and cell infiltration, anaphylatic shock
What are the roles of eosinophils in the allergic response?
Present in mucosal lining as protective role against parasites. Found LATE in allergic reactions. Produce toxic granule derived proteins and free radicals (which is usually for parasites - but will cause tissue remodeling). Eosinophils will also produce chemical mediators leading to epithelial cell activation and inflammatory cell recruitment and activation.
Why is there increased eosinophils during allergies (bypassed)?
Increased production in bone marrow due to IL-5 from Th2 and mast cells. The eosinphils are activated and infiltrate into tissue. There is decreased threshold for activation due to the sensitisation phase of IgE binding to FceR1.
What are the symptomatic treatment of allergies?
How do these work?
Adrenanine - Anaphylaxis (reforms tight endothelial junctions, relaxes smooth muscle as bronchodilator, increase HR)
Inhaled B-agonists - Asthma (Bronchodilators)
Antihistamines - hives and allergic rhinitis (Block histamine and reduces itching and decreases oedema)
Corticosteroids - provides broad non-antigen specific treatment of symptoms (suppresses chronic inflammation and broad immunosuppression by blocking gene transcription - multiple side effects and tolerance builds)
What is immunotherapy AKA desensitisation?
Administer increasing dose of allergen to induce T-cell tolerance.
Tolerance by: Anergy (decreased T cell proliferation), deviation of secreted cytokines, stimulate apoptosis and production of Treg cells.
What is Type IV hypersensitivity and what does it cause?
Cell mediated with heavy involvement of T cells and macrophages - mostly Th1 but sometimes CTL.
Generally caused by microbial infection, intradermal injection of protein antigens and contact with chemicals through the skin.
How does the sensitisation phase of delayed type hypersensitivity (DTH) work?
The antigen is taken up through the skin of mucosa that is taken up by APC and presented in the lymph node. This activates Th1 and CD8 T cells. The T cells leave the lymph nodes into the circulation and to the tissue of interest.
Why is there an accumulation of T cells and macrophages in DTH and what is its implications?
There is an accumulation because of antigen persistence. Leads to continuous release of the cytokines and chemokines. Means more infiltration, tissue destruction, adhesion molecules, monocyte production and ROS and RON.
What are three examples where persistent antigen can cause DTH?
- Contact sensitivity - poison ivy and TB tests will have central and effector memory cells triggered when re-exposed after previous sensitisation.
- M. Tuberculosis - Cannot clear organism
- Celiac Disease - Exposure to wheat products induce Th1 dependent immunopathology of intestinal wall.
How long does DTH take to manifest?
Usually takes a few days because the cells involved are slower
What is the mechanism of contact sensitivity?
First exposure to antigen will be taken up by APC leading to production of memory T cells. When re-exposed to the antigen the memory T-cells will activate and cause excessive inflammation (a lot of IFN-gamma and recruit macrophages)
How does M. Tuberculosis cause DTH?
Inhale TB that multiply in resisdent alveolar macrophages. This results in increase cytokine and chemokine production inducing monocyte influx. DCs migrate to lymph node that activates and recruits CD8, Th1 cells to the infection to further activate macrophages.
But after all of this the myocobacteria still persists leading to prolonged infection.
What is the result of contracting M. Tuberculosis?
M. TB induces granuloma formation essentially walling off the pathogen.
How does celiac disease cause DTH?
Results from hypersensitivity to components of gluten (gliadins). But it requires exposure unlike the persistence of TB. The celiac disease results in damage to the small intestine.
What kind of MHC molecule is found in patients with celiac disease?
>90% have HLA-DQ2
What is the mechanism of celiac disease and DTH?
The T cells recognise gliadin peptides through HLA-DQ2. Generally prefers to bind -ve AA side chains.
Unmodified gliadin proteins are +ve charged so cannot bind. But when tissue transglutaminase 2 will change gliadin proteins to -ve charged. Deamidated gliadin will bind to the HLA-DQ2 effectively now. Able to trigger immune response.
What is the definition of Asthma?
Chronic inflammation of airways associated with hyper-responsiveness leading to recurrent episodes of wheezing, breathlessness, chest tightness and coughing. Often reversible airflow limitations (not fixed airway obstruction).
What are the host and environmental factors that can influence asthma?
Host: Genetic, atopy, airway hyper-responsiveness (narrow too early and too much), Gender and obesity.
Environmental Factors: Indoor allergens, outdoor allergens, occupational sensitisers, tobacco smokes, air pollution, respiratory infection and diet.
What are the cells and mediators involved in asthma?
Allergen activate mast cells: to eosinophil and neutrophil leading to nerve activation.
Allergen activate macrophage/DC and Th2 cell.
Eventual responses lead to mucus hypersecretion, vasodilation (angiogenesis), plasma leak (oedema), bronchoconstriction and even subepithelial fibrosis.
What are the three primary responses in asthma?
Bronchospasm, airway mucosal oedema and mucus plugs (other mechanism to narrowing especially in smaller airways).
There are three contributors to narrowing of airways how do drugs target these mechanisms and do they act as preventers, relievers or controllers?
Airway smooth muscle contraction - reliever, controller and preventer
Bronchial oedema - Preventers
Mucus hypersecretion - Preventers
What is the impact of tidal stretch to the lumen size and muscles pulling on the airways?
Inflated airways the airway smooth muscles will open the airways the most. Deflated usually has very little pool and therefore is likely to have more resistance.
Where are the airway smooth muscles found?
They are arranged circumferentially around the airways that narrows the lumen when contracted. Found in the bronchioles.
There is no direct SNS but there is PS. The B-adrenoceptor comes from Adr.
How does the load and velocity of contraction affect airway resistance?
Load decreases during expiration causing increase in airway resistance and also increases likelihood of airways collapse.
Unloaded muscle shorten faster
What is the contractile mechanism of ASM? How is calcium level controlled?
Similar to skeletal muscle contraction. It is important to regulate calcium levels. Increase in calcium usually done by PLC and IP3that releases calcium stores.
Plasma Ca2+ ATPase, SR ATPase taking it back up into internal stores.
What determines the level of airway smooth muscle cell contraction?
The balance between contraction (ACh, HA, LTC4, LTD4) and relaxation (PGE2, adrenaline, PGI2)
How can calcium ion oscillation regulate smooth muscle tone?
Calcium will affect myosin light chain kinase. When the MLC is phosphorylated it becomes more calcium sensitive that can influence the contraction.
On the otherhand protein kinase A can dephosphorylate the MLC-phosphate.
What are the other airway smooth muscle dysfunction other than contracting?
Not only constrict and relax it also contributes to wall volume in airway remodeling and inflammation.
- Proliferation, migration, secretion of cytokines and secretion of ECM proteins.
Shows subepithelial collagen thickening, infiltration of inflammatory cells, increase mucosal vascularity and smooth muscle volume.
How to measure the severity of asthma?
FEV1 numbers
How do SABA (short acting B-agonists) work and their characteristics?
Salbutamol with rapid onset and B2 selectivity leading to bronchodilator. The adverse effects may be tremors, tachycardia and hypokaelamia.
Tolerance build up.
What is the mechanism of B2 agonists to reduce bronchioconstriction?
Increase in cAMP and PKA inhibits IP3 leading to reduced calcium levels. Reduced calcium levels means less MLCK (myosin light chain kinase) activation.
What are LABA and their characteristics?
Salmeterol are longer acting B2 agonists. The duration can be up to 12 hours. Usually used for prophylaxis and used in combination.
Monotherapy is associated with increase in mortality and morbidity.
How is B2-adrenoceptor activation regulated? Especially the desensitisation of these receptors?
Within seconds the receptors are phosphorylated that desensitises it by PKA.
Within minutes the receptors are sequestrated (internalised) - may be degraded or recycled to plasma membrane.
Within hours the receptors are down regulated by decreased mRNA stability and rate of transcription.
Are muscarinic antagonists good for asthma? How do they work?
Not generally used in asthma - more for COPD.
Less bronchodilation than B2 agonists.
Usually M3 receptors on ASM.
What are the rough levels of evidence that we should use for clinical practice?
Level I - Systematic review of randomised clinical trials
Level IV - Case series
Randomised controlled trials are the best
What is PICOT and its use?
P - Population
I - Intervention
C - Comparator/Control
O - Outcome
T - timing
Used to help determine what therapy to commence on.
What is internal validity?
Extent of validity of results that come from the study. Did it answer the question proposed? How well is the study design and data collection?
What is the point of randomisation in study designs?
Reduce confounding in studies. Try to make treatment groups identical in all aspects other than the intervention.
Reduces selection bias (investigators may assign subjects with bias)
What is stratified randomisation?
Break up key confounders and randomise people into those groups to make it more even. Makes the composition of groups even more similar and therefore reduces potential of confounding.
What is the purpose of Table 1 in studies?
Shows the base line characteristics of trials and more important should show that groups are evenly matched. The parameters are confounders.
What is the point of blinding in studies and its importance?
Non-awareness of intervention allocated. This will reduce information bias. Knowing what intervention you get can influence the outcomes.
What is objective outcome ascertainment?
Outcomes must be strict, standardised and have objective criteria. Multi-centre studies need to have a centralised process.
- Reduce information bias.
What is the intention-to-treat analysis and the point of it?
Assume subjects remain in the groups they were randomised in. This is to reduce selection bias.
Since drop outs selects for healthier group in drug group. Misrepresentation of new drug being better than placebo.
It always gives underestimate of the treatment effect - gives us more confidence of the results.
How to interpret statistical analysis?
P value and confidence interval (this gives precision)
P value - gives probability that chance gave us the results. Conventionally set it as p < 0.05 significant.
Confidence interval: 95% chance the true value lies within this particular interval.
What is the number needed to treat?
Number of people needed to undergo treatment to prevent one outcome.
Marker of intervention efficiency.
How to calculate number needed to treat?
NNT = 1 / (absolute risk or rate reduction)
What affects the NNT (number needed to treat)?
Affected by relative effect (often constant) and the underlying likelihood of outcome.
It is important to work out what the chance of the outcome is of occuring.
What is meant by external validity?
How similar is the PICOT in the study to my patient? Should I use the particular intervention for my case specifically?
What are the main functions of the lungs?
Oxygen the pulmonary arterial blood, remove carbon dioxide from blood and maintain acid-base balance.
What is the metabolic requirement at rest and during exercise?
At rest (BMR) - 250mL/min O2 and 200mL/min CO2
During exercise - >4000mL/min O2 and >4000mL/min CO2
What carries oxygen in the blood?
4 oxygen molecules per Hb molecule
How is CO2 transported around in the plasma?
- Dissolved - 10%
- Attached to proteins (include Hb) - 30%
- Bicarbonate - 60%
Where does the exchange of oxygen and carbon dioxide occur over?
Alveolar and capillary membrane (AC membrane)
What is the alveolar-capillar membrane composed of and its characteristics?
Very thin layered with two cells (alveolar and endothelial). Has a large surface area. These two qualities make it ideal for gas exchange.
What is the rate of diffusion across the AC membrane driven by?
Fick’s Law
How long does it take for the oxygen to diffuse into the venous blood?
0.75 seconds that is normal for rest. During exercise there is only 0.25 seconds available.
When is gas exchange the most procifient?
When there is ventilation to perfusion matching.
What is the anatomy of the airways briefly?
Upper airway - nose, mouth, pharynx and larynx
Trachae and bronchi.
Multiple branching of bronchi into bronchioles eventually terminating into alveoli.
What are the respiratory muslces involved in inspiration and expiration?
Inspiratory - diaphragm, external intercostals and sternocleidomastoids
Expiratory - Internal intercostals and abdominal muscles
How do our lungs inflate with air?
Inspiration via negative pressure created. Contraction of diaphragm increases longitudinal and lateral dimensions of the thorax (negative intra-pleural pressure).
Contraction of the external intercostals increases the AP diameter of the thorax (negative intra-pleural pressure).
Is inspiration and expiration generally passive or require use of muscles?
Inspiration requires muscle to create the negative pressure but the expiration is generally passive because of the lung recoil to push the air back out.
What makes up the work of breathing?
- Resistive - the airflow through bronchi
- Elastic - the expansion of lungs and chest wall (lungs have some degree of stiffness and want to collapse down).
What are the different pressure levels of gas found in the blood and the pH level normally?
PO2 - 100mmHg
PCO2 - 40mmHg
pH - 7.4
What can you notice when you breath through an obstructed airway?
Increased sensation of breathing, increased use of respiratory muscles, active exhalation, longer inspiration, longer expiration and reduced maximum ventilation.
Why do we feel an increased sense of breathing?
There may be an increase in load (such as stiff lungs, narrow airways, chest wall and diaphragm that makes it harder to breath).
There could be a larger drive to breath (usually by receptors or even when we purposely hyperventilate).
There is a larger work required of our body. Such as when we exercise but we perceive it as normal.
What is increased in the sensation of breathing usually referred to as by people? When is it perceived as a sensation or symptom?
It is breathlessness. Sensation when it is normal for it to occur whereas symptom when it is inappropriate.
What is the work of breathing usually like at rest? What does it involve?
Normally very low at around 3% of total oxygen usage. Involves stimulation of phrenic nerve for diaphragm and external intercostal muscles through intercostal nerves. Increasing volume of thorax will lead to generation of negative intra-pulmonary pressure.
How is the work of breathing affected when there is an airway obstruction?
Respiratory muscles need to generate higher pressures to overcome the obstruction to air flow (resistive work of breathing). It also makes expiration become active.
What are the important consequences of increased work of breathing?
- Recruiment of accessory muscles (scalene and sternocleomastoid muscles).
- Increased oxygen consumption by respiratory muscles.
- Risk of respiratory muscle fatigue if the airway obstruction is severe.
Respiratory muscle fatigue is a common cause of ventilatory failure - what do we define as ventilatory failure?
PaO2 <60mmHg and PaCO2 > 50mmHg
What are the different lung pressures during breathing?
Intra-alveolar pressure < Patmospheric during inspiration
Intra-alveolar pressure > Patm during expiration
Intra-alveolar pressure = Patm at the end of inspiration and expiration
Intra-pleural pressure is ALWAYS < intra-alveolar pressure because of the elastic recoil of lungs and chest wall.
Explain how we do a spirometry and what we can get out of it, FEV1 and FEV1/FVC?
Spirogram involves breathing in TLC then exhaling as quickly and much out as possible. The graph will increase significantly during FEV1 (70-80% of FVC) until it stabilises to give FVC.
Airflow obstruction will generally give a more linear curve meaning that exhalation is much longer.
How else can we measure prolonged inspiration and expiration? How does the test work? How do we interpret it?
Use of flow-volume loops. Involves taking a breath in to TLC then blow out as quickly as possible - once it has been exhaled the patient needs to breath in through the tube again to TLC.
Different locations of obstruction will lead to different flow-volume loops.
What are the summary of mechanical effects of airflow obstruction?
- Increased sensation of breathing
- Increased respiratory muscle effort
- Active exhalation
- Prolonged inspiration and exhalation
If the respiratory muscles become fatigued or if metabolic demand exceed ventilatory capacity during exercise - what are the changes to PO2 and PCO2?
There will always be a decrease in PaO2 and increase in PaCO2
What is ventilation perfusion matching?
Gas exchange is most efficient when this matching is 1 for individual AC units (alveolar capillary unit)
V/Q scan in normal patient compared to those with COPD?
Normal people have even distribution and COPD has mismatch between the two.
What are the consequences of V/Q mismatch?
Not all oxygen binds to Hb molecules - reduce PaO2so that some blood returning to the LA is not fully oxygenated.
Usually as a result from less ventilation than perfusion.
What is meant by a shunt?
Extremely low form of V/Q unit where there is no ventilation at all and V/Q = 0.
What happens to compensate for low V/Q units?
Usually results in vasoconstriction of blood around the areas with low ventilation to reduce hypoxaemic effects.
Sometimes the vasoconstriction may elevate the pulmonary artery pressure.
What happens with V/Q mismatch when there is a high V/Q unit?
Usually results in wasted ventilation because there will be more ventilation of the units than required to oxygenate the blood.
- Leads to increase in physiological dead space
How can we generally measure the integrity of A-C membrane?
Measure the CO2 levels.
Describe asthma and the two ways it causes airway obstruction.
- Bronchial smooth muscle constriction which is responsive to B agonists, anticholinergics, methyl-xanthines.
- Airway inflammation: responsive to corticosteroids, leukotriene antagonists and mast cell stabilisers.
What is COPD and how does it obstruct airways and its consequences?
COPD is smoking related disease that causes inflammation of bronchial mucosa, loss of elastic support of small airways and destruction of the alveolar-capillary membrane.
- Collapse of small airways -> airflow obstruction.
- Impaired gas exchange -> because of VQ mismatch and loss of A/C membrane
- Reduced capillary bed -> pulmonary hypertension
How is AC membrane integrity used to differentiate COPD and asthma?
Typically COPD has a lack of AC membrane integrity.
How can we quantify the Alveolar-arterial gradient for oxygen?
PAO2 = PiO2 – PACO2 / RQ
PaCO2 = PACO2 and RQ = 0.8 and PiO2 = 150 at sea level.
Then for gradient you need PAO2 - PaO2
Normal levels < 15-30.
What is the difference between the conducting and respiratory parts of the respiratory system?
The conducting part is what carries the air along whereas the respiratory part is where gas exchange actually occurs.
What is the nasopharynx?
This is the nose area.
What are the roles of the sinuses, olfactory epithelium and turbinates in the nasopharynx?
The sinuses is used for phonation and conditioning air. Olfactory epithelium is for the sense of smell. Turbinates warm and moisten the air so that the air will not dehydrate the airways.
What is the epiglottis and larynx and its functions?
The epiglottis and larynx divert food away from the airways. Larynx is involved in phonation (speech).
The larynx is the uppermost part of the trachae.
What is the respiratory epithelium?
Lines the airways and much of the nasopharynx (lines conducting part instead of respiratory part)
Pseudostratified epithelium with ciliated cells, secretory cells (goblet and deeper glands) of mucus and sensory cells to initiate coughing to expel irritants.
Why do we have mucus secreting cells and ciliated cells?
This is to protect against air that have dust particles, fungal and bacterial spores.
How do goblet cells and cilated cells aid in the protective mechanisms?
The mucus layer traps particles that are then swept up by the cilia to the epiglottis. Ends up in the stomach for sterilisation.
Smokers who have damaged cilia cells rely heavily on coughing to shift the mucus upwards of the lungs.
What is the trachae and its structures?
Long tube reinforced with hyaline cartilage. The cartilage is in C-shaped formation with smooth muscle bridging it.
The trachae has three layers - mucosa, submucosa and adventitia.
What is the difference between the mucosa and submucosa layers and what are found in each layers?
Mucosa is much thinner than the submucosa layer. Submucosa is much broader with connective tissue and glands that secrete mucus.
What is found in the adventitia layer of the trachae?
It contains cartilage and outer layer of connective tissue.
What is the bronchi and its structures that differentiate it from the trachae?
The trachae splits into five different bronchi that lead to different lobes in the lungs (3 - right and 2 -left).
Initialy looks like trachae but with thinner walls. As you progress down the airways cartilage rings become cartilage plates instead (lose C-shaped rings).
Smooth muscle, glands and lymphoid nodules still present.
How to differentiate a bronchiole from a bronchi and what structures does it have?
Bronchioles no longer have the cartilage. Over the length of the bronchiole they being to lose goblet cells and ciliated columnar cells and gain Clara cells.
Still have radial connective tissue, smooth muscle and ciliated cells extend further down than goblet cells (lose the goblets earlier).
What are clara cells and what do that do?
These are columnar to cuboidal cells with short microvilli (instead of cilia). Generally found deeper in bronchioles.
They secrete surfactants to destroy surface tension (causes alveoli to collapses). They may also neutralised toxin.
What are terminal bronchioles?
Last level of the conducting system. No golbet cells. Clara cells plus cuboidal epithelium with some cilia. There is one or two layers of smooth muscles and they give rise to respiratory bronchioles (first site of gas exchange).
What are respiratory bronchioles and what do they do?
First respiratory structures to appear where alveoli will appear intermittently. Alveoli are thin walled pouches. The epithelium of the respiratory bronchiole are made up of cuboidal to squamous cells.
What are the alveolus for and what are their structures?
Surface for gas exchange. Lined with simple squamous epithelium. The wall contains many pulmonary capillaries (deoxygenated blood within them). Also the individual alveoli are connected by pores so that they become connected.
What is the interalveolar septum and what is it made of and function?
This contains reticular fibres and elastin fibres between the alveoli. They prevent the alveoli from collapse during breathing when negative pressure is generated. Positive air pressure helps it stay open.
What are the pulmonary capillaries surround the alveoli and its structure?
They form dense anastomising network of vessels for exchange of gases. The pulmonary epithelium is very thin.
What are type I pneumocytes?
These are present in alveoli made up of simple squamous epithelium. It provides about 95% of the surface area of alveoli. It provides the exchange surface. The basal lamina is prominent because it limits the gas exchange process.
- There are tight junctions between the pneumocytes to limit ECF leakage.
What are type II pneumocytes and their role?
More numerous than type I but only found on 5% of the surface area. These are cuboidal cells in the angles between alveoli. They consist of short microvilli and lamellar bodies.
- The lamellar bodies secrete surfactants to prevent collapse from surface tension.
How are the pneumocytes replaced? Are they replaced?
There is turnover of pneumocytes that involves Type I dying and being replaced by stem cells.
The Type II can divide and give rise to new type I and II as required (stem cells).
What is the blood-gas barrier?
This is where the exchange of air takes place across the Type I pneumocyte and endothelial of the capillaries.
What contributes to the blood-gas barrier?
Contains mucus, surfactants, type I pneumocytes, basal lamina, connective tissue, basal lamina, endothelial cell then finallay plasma.
The thinnest barrier is when there is essentially no connective tissue between the two basal laminas.
What are intra-alveolar macrophages?
These are macrophages that exist in the alveoli and essentially outside of the body.
What are the outcomes for intra-alveolar macrophages when they have ingested particles?
They can migrate up the airways until they are carried away by ciliated cells. Or some macrophages end up in the interalveolar septum with the particles they ingested (return to body and eventually die and release their contents).
What is the significance of the visceral pleura having blood and lymphatic vessels?
There is abundant lymphatic systems in the pleura to drain fluids. But there are also vessels opened on the surface of the pleura (releases fluid into the space). The consequence of this is that tumour cells can use this pathway to metastasise.
Why is there a lag phase between the innoculation of virus until we see growth and how much growth do we observe from viruses?
The lag phase is when the virus components are being synthesised and eventually assembled together to form viable viruses. The number of viruses produced are enormous.
What are the steps involved in viral replication?
Attachment, penetration, uncoating, genome replication, RNA synthesis, protein synthesis, assembly and release of viral particles.
How do viruses attach to the host cells?
The viral attachment protein must bind to a receptor found on the cell surface of the host. This could be proteins or glycoproteins expressed on the surface (these receptors are just used for normal cell processes)
Why would some viruses use two attachments to bind to the cell surface? Give an example of one.
HIV viruses uses two different cell receptors. gp120 binds to CD4 as primary receptor. This induces conformational change in the glycoproteins - gp41 now binds to CCR-5 as a secondary receptor.
How do viruses penetrate into the host cells?
This is achieved via two ways.
- Lipid envelope viruses fuse with the host cell membrane and then releases the virus nucleocapsid directly into cytoplasm.
- Other viruses enter the cell via endocytosis
What is the process of virus uncoating once it has penetrated the cell?
It just refers to the release of viral genome from its protective capsid.
What is an example of a virus that enters the cell via the endocytosis pathway?
Togavirus does this - it triggers endosome release when the pH is low.
What happens during the amplification phase of the viral genome and proteins?
Nucleic acid replication will produce new viral genomes. DNA replicate in nucleus and RNA based virus replicate in cytoplasm.
mRNA is produced and used to produce proteins.
What machinery is available in the host cell for transcription, translation and nucleic acid replication?
DNA dependent DNA polymerase, DNA dependent RNA polymerase and ribosomes, tRNA and AA.
- no RNA-dependent RNA polymerase present for RNA invading viruses.
What is meant by plus sense strand of virus? And what is meant by negative?
Means the strand of genetic material is the same as mRNA. Negative sense means that it is the complementary base sequence.
What is the characteristic of Polio virus genome?
Linear, single stranded, plus sense RNA.
What are the two possible outcomes of plus sense RNA viruses, what pathway does it typically go with?
The RNA can be replicated to produce more mRNA but that would require RNA-dependent RNA polymerase.
Another pathway is that it will be directly translated into proteins. This protein is then autocleaved by itself to produce structural coat proteins, proteases and RNA POLYMERASE.
What happens when the +RNA viruses are translated and produce RNA polymerase?
The RNA polymerase can now enter the through the other pathway. It will allow the RNA to replicate to form new plus strands. It will produce negative and positive strands.
How would -RNA viruses translate if there are no RNA polymerase in the host cells?
The -RNA viruses carry RNA polymerase with it.
Each virus must produce mRNA to translate into proteins. There are different types of viruses with different approaches to these (Baltimore classification)
Do DNA viruses need to carry their DNA-polymerase?
The DNA viruses do not need it because the host cells have the enzymes already.
Do RNA viruses need to bring along its own RNA polymerase?
Negative strands - must carry their own polymerase
Positive strands - do not need to carry it
What is the translation and packaging process involved for viral proteins?
Translation of the proteins occur on the ribosomes in cytoplasm. After the polypeptide is formed it is cleaved by virus-coded proteases.
Glycosylation of envelope glycoproteins occur in RER and golgi vesicles -> allows them to be deposited on cell membrane.
Explain the assembly and release of viruses from the host cell.
For non-enveloped animal viruses: All have icosahedral structure. It can simply spontaneously assemble with capsid proteins around the nucleic acid genome. Final cleaving will need it to produce mature infectious virions. It will accumulate in the cell and eventually lyse.
For enveloped viruses: Release occurs by budding from the cell surface. Patches of viral envelope glycoproteins accumulate on membrane. Capsid proteins and nucleic acid condense directly adjacent to cell membrane. The nucleocapsid then bulges out and forms a new enveloped virion.
Another pathway for enveloped viruses is to use secretory pathway to exit the cells. Enclosed in Golgi derived vesicles that are then released through fusion of membrane.
What changes can occur to the host cell when the virus infects it?
- Lytic infection (overwhelming the cell - enteroviruses, reoviruses): Fast release and death of cell.
- Chronic inflammation (Hep C): Slow release without cell death.
- Latent infection (herpesviruses): No harm to cell and can emerge later as lytic infection.
- Transformation to tumour cells (oncogenic retroviruses)
What is cytopathic effects (CPE)?
This is the morphological changes that can be seen due to infection through a light microscope.
What are inclusion bodies?
Inclusions are accumulated areas of viral proteins at the site of viral assembly.
Why do some viruses cause cell transformation - especially oncogenic transformations?
Viruses encode for oncogenes that is associated with tumour production. These oncogenes were meant to promote growth promoting properties but their expression can lead to uncontrolled proliferation. Other viruses can affect tumours because of the cellular version of the oncogene is activated.
What are some ways the viral genetics can change?
Mutation (errors in RNA replication due to the lack of proof reading - or two viruses infect the same cell), recombination (exchange of stretches of nucleic acid between genomes of SIMILAR sequences especially DNA viruses), reassortment (swapping of segments for viruses that have segmented genomes - with many different properties of viruses).
What can halt the infectious process?
Antibody blocks the uptake and/or neutralises progeny virus. Killing of the infected cells by cytotoxic T cells, NK cells or antibody mediated processes. The interferons released will initiated a large number of anti-viral mechanisms. Blocking the replication cycle by using specific antiviral drugs.
What are the uses of nucleoside analogs e.g. Acyclovir?
It is used for herpesvirus infections. Works by attaching the nucleoside analogue to the extending DNA strand. But it does not have the 3’ OH group so it can no longer extend the chain further.
Acyclovir is an guanosine analogue. It is specific for Herpes because the nucleoside analogue must be phosphorylated three times before it can be attached. The virus’ thymidine kinase is required for this step - giving specificity for infected cells.
What are the general principles of viral pathogenesis?
Must gain entry to body, multiply, spread, target appropriate organ.
To maintain nature viruses it must be shed into environment, taken up by arthropod (insect) vectors or needle and passed congenitally.
Viral replication can be local or systemic. It will either be cleared or persist.
The virus infection location will be determined by whether or not they have the receptor for the viruses.
What are the different routes of entry for viruses?
Conjuctiva, respiratory, parenteral inoculation, alimentary (food and digestive) tract, urogenital tract and skin.
Enters through epithelial cells with mucosa. Other areas have dying cells and keratinisation making it a bad environment for viruses.
How do viruses infect the respiratory tract and what is the significance of the respiratory tract and viral infections?
Most important site of entry. Usually from aerosal inhalation or transmission of infected nasal secretions. The smaller the virus the further down it will lodge in the airways.
Viruses will attach to specific receptors on epithelial cells. It can either localise or spread away.
What are the barriers to infection found in the respiratory tract?
Mucus, cilia, alveolar macrophages, temperature gradient and IgA.
The different site of viral replication in the respiratory tract will cause different syndromes. What are they? And the likely viruses?
Upper respiratory tract infection - Rhinovirus (better in cooler temperatures), coronavirus and adenovirus.
Pharyngitis - Adenovirus
Influenza-like illness - influenza virus, RSV (respiratory synctial virus).
Croup (larynx and trachae) - Parainfluenza
Brochiolitis - RSV and parainfluenza 3
Pneomonia - RSV, parainfluenza 3, influenza virus and adenovirus.
What is the histological morphology of RSV?
Respiratory synctial viruses in the lungs are that the infect virus cells will fuse together to form a synctial (multinucleated).
How do measles virus infect children, what do they infect, what happens after infection and why is it so contagious?
Primary replication in URT epithelial cells. Infects local macrophages, lymphocytes and DCs through receptors. They then drain to the lymph nodes and enter the circulation. Eventually returns to the epithelial cells on the lungs and mouth.
Rash is due to the immuno response not the viral infection.
Transient immunosuppression since it affects immune cells.
What are the barriers to infection found in the alimentary tract?
Constant movement of contents, mucus, stomach acidity, intestinal alkalinity, proteolytic enzymes from pancreas, lipolysis of bile acid, IgA and scavenging macrophages.
What are the properties of viruses that infect the intestinal tract?
They must be acid and bile resistant (therefore have no envelope).
If viruses do not have receptors for the epithelial cells it must enter via a breach of the epithelial surface (HIV - through abrasions of rectal route).
What is an example of virus that causes diarrhoea and how?
Rotavirus - destroys walls of the stomach or other mechanisms.
What are some viruses that enter through the intestinal tract but cause systemic infections?
Poliovirus and Hepatitis A
How does the virus infect the alimentary tract (entry)?
M cells ingest the virus and delivers the antigens to underlying lymphoid tissue by transcytosis. M cells are found between enterocytes with tight junctions.
Other viruses can infect and destroy M cells. This creates a gap for viruses to enter the intestinal tract.
How do rotaviruses cause intestinal tract infections?
They have triple shelled capsid and infect and destroy epithelial cells of the intestinal vili and the M cells then cause inflammion and diarrhoea.
Why does diarrhoea occur (mechanism)?
Destruction of enterocytes decreases absorption. Also secretion from the virus NSP4 proteins from infected cells make the diarrhoea even worse. NSP secretes fluids from the remaining cells.
Usually death through dehydration.
How do intestinal tract infections lead to systemic diseases?
Enters the body then replicates at the primary site. From here it can move into the blood stream (viraemia) and replicate in lymph nodes such as Peyer’s Patch. It will then reach the secondary viremia target tissue causing disease.
Moves to meninges, CNS, skin and muscles.
Which of the two viruses are more likely to cause systemic disease through the intestinal tract, picornavirus and enterovirus?
Picornavirus
What are the other routes of human infections?
Transcutaneous route (bypassing skin) - minor trauma, injection via needles or blood products or insect/animal bites.
Genital tract.
Conjuctiva (very rare route of entry).
How can the virus spread within the body itself?
Local spread around epithelial surfaces. It can invade the subepithelial layer then invade the lymphatic system. Spread through the blood - also known as viremia. It is also able to spread neurally.
What is the pathway for the viruses to move from the epithelium to the blood?
Epithelium to lymph nodes to epithelium. This is also so that the viruses will face the lymphatic/immune system first. To trigger the immune system earlier.
What is meant by viremia?
This is when the viruses are free in the plasma.
What is meant by primary and secondary phase of viremia?
These phases refer to the growth phases. Secondary phase is when it infects other organs that can replicate enormous amounts before re-entering the blood stream again. The goal is to make enough to escape the immune system.
How are viruses neutralised typically?
Neutralised by developing antibody response that is then removed by the macrophages (1-2 weeks).
Describe the typical course of viremia and its timeline in relation to the immune system response? Also note where the primary and secondary viremia is.
Invades epithelial cells and multiply. Moves to lymph nodes then multiples. It becomes primary viremia when it moves into the blood initially. Moves to other organs and replicates there. Returns to blood (secondary viremia) and moves to the skin and multiplies.
Typically takes about 6 days for it to leave the skin so it would have avoided the immune system altogether.
Viruses are able to infect the fetus, what are the characteristics needed for this to occur?
The virus must be able to cross the placenta. The fetus may die from cytocidal viruses such as small pox.
What are the outcomes of viruses infecting the fetus?
It can cause death or abortion if it is cytocidal. It may not kill the fetus but will cause abnormal development - especially rubella and CMV (cytomegalovirus).
Can babies be infected during birth?
Yes! There can be many other infected sites (even faeces) that the baby may come into contact during birth.
What is the importance of viremia and its impact on a fetus?
The viremia may cause the fetus to develop an immunological tolerance to the virus (will no longer recognise it to be foreign in later life).
What is the result of congenital rubella syndrome?
Rubella slows down the rate of cell division leading to impaired growth and organ development in the first trimester.
Microcephaly, heart defects, cataracts and deafness.
What determines where the virus will infect?
The right receptor for the virus, temperature, pH, ability to replicate in macrophages and lymphocytes (to other tissues), polarised release (depends if viruses leave apically or basolateral - more systemic) and the presence of activating enzymes.
How does the virus cause viral-induced damage to the tissues and organs?
Death of cells directly from viral replication (cytocidal virus), death due to the toxins released by the viruses, initiation of apoptosis and loss of function of the cells.
What are the consequences of the immune response against viruses?
Immunopathology - virus elicits immune response, symptoms may be fever (IL-1 and TNF) and enlarged lymph nodes.
Antibody-mediated pathology - antibody dependent enhancement of infection as well as antigen-antibody complexes (cannot clear the viruses).
T cell mediated pathology - CD4 T cell mediated responses causes some viral rashes (measles) because it induces cytokines to recruit eosinophils. Kidney damage due to deposition of Ag-Ab complex.
CD8 T cell mediated responses contributes to liver damage.
Autoimmunity - molecular mimicry can affect myelin basic protein or heart muscles. Polyclonal B cell activation.
Immunosuppression - HIV replicates in CD4 T cells amd kills them. Measles temporarily immunosuppresses - stops T cell proliferation by infected DC - suppressing IL-12. This will lead to susceptibility to secondary infections.
What is the interplay between cells of innate immune system to viruses?
Virus infects cells and are taken up by macrophages/DCs. They will both release IFN alpha/B (type I IFN), macrophages will produce pro-inflammatory cytokines and IL-12.
Combination of both IL-12 and IFN alpha/B to stimulate NK.
NK cells leads to lysis of virus-infected cells and are the dominant sourceo f IFN-gamma (T cells as well).
What are the outcomes of type I IFN?
Inhibit viral replication, activate NK cells, enhance MHC I expression and are produced by virus-infected macrophages, DC and tissue cells.
What are the outcomes of Type 2 IFN?
Inhibits viral replication, activates macrophages, enhances MHC Class I and class II expression and produced by NK cells (and T cells).
How have viruses evolved to evade immune attacks?
- Not being recognised by the immune system
- Interfering with functioning of particular immune mechanisms.
Large complex DNA viruses have acquired many other strategies to evade the immune system (Herpesviruses and poxviruses).
What are the strategies viruses use to evade the immune system?
Antibody and T cell latency, antibody - antigenic variation, T cell priming by DC, Tc cell recognition, NK cell recognition, IFN, cytokines (blocking of cytokine production, apoptosis inhibition and complement.
How do viruses achieve antigenic variation?
Change in antigenic structure of viruses due to spontaneous mutation (errors in RNA replication - no proof reading) that are then selected by escape neutralisation.
Antigenic drift can occur within a single patient for long term infections such as HIV.
How can viruses prevent DCs from priming T cells?
Immature DC process the pathogen and becomes matured. It will then be able to interact with naive T cells to activate them.
- Block cytokine induced maturation of DCs
- Blocks signal transduction within immature DC
- Blocks TLR from initiating signal transduction to maturation (the signal pathway binds to a homologue instead)
Block T cell stimulation by DCs.
How are virus antigen displayed on infected cells?
Usually virus antigens are expressed on MHC I. Achieved by viral proteins made in cytosol that enter a proteosome complex to be cleaved. It is taken up to the ER via transporter of antigenic peptides (TAP). It is processed with MHC to be expressed on the cell surface for recognition.
What are the mechanisms viruses can use to evade CD8 T cell recognition?
Viruses can cause the MHC I to be endocytosed back into the cytoplasm. HIV.
Antigenic variation in the virus displayed can allow viruses to escape the T cells. The T cells will raise its number for the wrong antigen. HIV.
Viruses can bind to cytosolic side of TAP and prevent peptides moving into ER - HSV. No receptors will be no the surface.
Viruses can bind to TAP on the luminal side to prevent peptide entering ER - CMV.
The peptide complex is retained in ER - adenovirus. (Anchors to ER so it cannot reach surface).
Infected cells will have virus disrupt the proteosome complex so fragmentation cannot occur. EBV.
Decrease in class I gene transcription - HIV, RSV and adenovirus.
What are the consequences of activating NK cells?
Kill virus-infected cells non-selectively. Recognises cell surface receptors that result from virus infections to send a killing signal.
The MHC I molecules send inhibitory signals to the NK cell. If the MHC I cell is absent or reduced the NK cell will not have inhibitory signals engaged and end up killing the target cell.
How is NK cell activation controlled?
Balance between activation and inhibitory stimulation.
MHC Class I molecule activate inhibitory receptor. Other ligands on cell activate activation receptor. Viruses that reduce MHC I expression can except CD8 T cell recognition but become more susceptible to NK killing.
What are the ligands that are found to stimulate activation receptors?
NKp44, NKp46, NKG2D receptors will bind to its ligand.
What are some ways viruses can affect NK activation?
Present the presentation of ligands to activate NKG2D by retaining it in the ER - Murine CMV. (Decrease activation ligand on surface).
Present MHC Class I-like molecule on the surface of infected cells so it delivers negative signal to NK BUT does not present peptides to CD8 T cells.
What are the roles of IFN in the anti-viral mechanism of the body?
Soluble factor released from virus-infected cells that inhibit viral replication in neighbouring cells.
Type I and II IFN stimulate signalling pathway to upregulate transcription/translation of certain cellular proteins. Especially PKR (protein kinase R) that has antiviral activity.
How does the upregulation of PKR provide anti-viral activity?
IFN will aid in the activation of PKR inactive state. But it requires autophosphorylation to become active where dsRNA is a cofactor. dsRNA is only found in the presence of RNA viruses during replication.
The PKR active state will cause elF2alpha to become inactivated. This will stop the initiation of translation to occur (both viral and cellular).
Why do we need dsRNA to activate PKR?
Simply because RNA needs to be present to allow the PKR to hook around and autophoshorylate.
How can viruses overcome the PKR that is posing a threat to viral replication?
Viruses produces small RNA that bind to PKR so it prevents dsRNA from binding - EBV, adenovirus.
Virus can encode proteins that bind to dsRNA preventing it from activating PKR - reovirus, vaccinia.
Virus encoded homologue of elF2 so it competes for PKR inhibition of the true elF2alpha (by phosphorylation) - vaccinia.
What are some genetic factors that can influence the susceptibility to viral infections?
Inherited defects such as Ig class, polymorphism in the genes controlling immune responses, IFN inducible genes and receptor genes (such as CCR5 for HIV as secondary receptors).
What are some non-genetic factors that influence susceptibility to viral infections?
Age - newborns and the elder are more susceptible, malnutrition - decrease resistance, hormones, dual infections - more severe disease.
What are the overall outcomes of viral infections?
Fatal, full recovery, recovery buut permanent damage (such as cancer), persistent infections (not completely cleared and can resurface to cause disease).
Where is the anatomical location that distinguishes between upper respiratory tract from the lower respiratory tract?
The epiglottis.
What part of the respiratory tract are the normal biota located?
URT - Has own normal biota
LRT - Does not have a normal biota
Also paranasal air sinuses and middle ear will be free of microbiota in the URT.
What is the prevalence of pathogens in the respiratory tract, those that are found in >50%?
Viridan streptococci (not a pathogen in respiratory tract but can cause endocarditis), Neisseria species, Corynebacterium species, Gram Negative anaerobes (majority), H. Influenza, C. albicans and Strept. pneumoniae (15-85% - large range of population it affects).
What is the prevalence of the pathogens found in the respiratory tract, that are uncommon (1-10%)?
Strept. pyogenes (Group A) and meningococci
What is the prevalence of pathogens found in the respiratory tract, uncommon ones (<1%)?
Enterobacteria, Pseudomonas, C. Diphtheriae (Unique to humans - humans are the only carriers)
What are some pathogens that are found in the latent state, in the lungs and lymph nodes?
Lungs - P. jirovecii (carinii - causes PCP (pneumocystis pneumonia) this is an AIDs dependent infection) and M. Tuberculosis.
In lymph nodes and sensory nerves - CMV, HSV and EBV. After the primary infection with these viruses they become resident and when you become immunosuppressed it will resurface as blisters.
What are the different components of the forest plot?
Test for heterogeneity? Line of Null effect? How to interpret the squares for effect size of study? Pooled Effect?
For heterogeneity tests we want P>0.05 because that would indicate low heterogeneity.
Line of null effect on the right uses ‘1’ value as ratio. Whereas the line on the left will indicate ‘0’ value as absolute changes.
Interpreting effect size of study - larger area of square gives relative weighting of contribution. The width indicates the confidence interval (line is used if sample size is small).
When does the diffusion limitation of oxygen become apparent?
Usually occurs during exercise with less severe disease because the exercise highlights the limitation (less transient time). It is typically still fully oxygenated at rest.
However at rest it is highly unlikely to see diffusion limitation. It only occurs in severely abnormal AC membrane.
What is meant by emphysema?
This is the loss of AC membrane that will cause diffusion problems. The loss of tissue makes the lungs more compliant (also loss of elastic tissue). So we usually see the barrel chest appearance.
What are the different compliances of lungs and typically what are they caused by?
Increased in compliance - emphysema
Decreased in compliance - Pulmonary fibrosis
What is the ventilatory response to exercise?
Ventilation will increase with work to maintain PaO2 and PaCO2. Once you are beyond the anaerobic threshold you will increase ventilation more.
Ventilation is matched to oxygen consumption and CO2/H+ production.
What is the histological characteristics of glandular tumour cells?
Formation of glandular lumina, formation of mucin (lots of mucus) and signet ring cells (mucus within the cells).
Describe the progression from normal epithelium to invasive neoplasm.
Epithelial are the most common cancer and it begins with intraepithelial neoplasia - can treat it before the cancer becomes invasive. Normal epithelium as simple columnar (can be stratified squamous) in the gut and there is the basement membrane. One of the stem cell in the epithelium develops multiple mutations and starts off in one cell. Mutations can arise from carcinogenic agents, microbes, nutrients (guts) or inherited. It then becomes multiple cells that proliferate. The cells become pleimorphic because of different nuclei shape and size, mitosis (dysplasia or intra epithelium neoplasia), but it still remains in the epithelium. When it becomes very severe it becomes in situ neoplasm. If one of these cells get mutated to express MMP will allow the cells to lose its cohesiveness and escape through and become invasive neoplasm.
Why is the cell cycle so important in cancer? Where are the checkpoints found?
It regulates growth and mitotic phases. There are many cell cycle controls that could lead to increased proliferation.
End of G2, middle of M, end of G1 and during S.
Oncogenes inhibit the checkpoints (RAS), whereas the tumour suppressors p53 enhance the check points.
What are the predisposing factors to lung carcinoma?
Tobacco smoking, asbestos and arsenic.
If you are a non-smoker you are most likely going to contract adenocarcinoma.
