T5 - IE1 - Pulmonology - Ostrom + Munjy - Integrated Pathophysiology of Asthma

Intermittent asthma symptoms

≤ 2 days / week

Mild persistent asthma symptoms

> 2 days / week but not daily

Moderate persistent asthma symptoms

daily

with REDUCED 5% FEV/FVC

For asthma go with __________ treatment for symptoms and ________ _______

- highest (treatment for symptoms)

- step down

i.e., start with step 5 and go down

Severe persistent asthma symptoms

Throughout the day

> 1x week night time awakening

Asthma

paroxysmal dyspnea accompanied by wheezing caused by a spasm of the bronchial tubes or by swelling of their mucous membrane

Paroxysmal dyspnea

sudden, recurring episode of difficulty breathing

seen with chest tightening, wheezing, coughing

Asthma is mild in ____% of population; ____% need regular medication

- 10(%)

- 2(%)

Asthma mortality is _______

- (is) rare

increasing over past 3 decades

Asthma is a $______ ______________ market industry

- ($)56 billion

For > 50% of patients, costs for asthma are __ ___% of family income

- > 18(% of family income)

Asthma triggers

environmental exposure

occupational exposure

drugs

foods

additives

diseases (e.g., infectious disease and toxins associated with ID)

cold air

Two phases of an asthma attack

early

- bronchospasm

inflammation

- late

Early phase of an asthma attack

bronchospasm

Late phase of an asthma attack

inflammation

Pathologic cascade of asthma figure

Pathologic cascade of asthma steps

1. allergen-induced bronchoconstriction

2. activation of immune cells

3. remodeling of airway tissue

4. hypercontractile status (due to hyperplasia / hypertrophy)

Pathologic cascade of asthma step 1: __________-induced ____________

- allergen(-induced)

- bronchoconstriction

Step 2. Activation of immune cells

Pathologic cascade of asthma step 1: allergen-induced bronchoconstriction

step 2. activation of ____________ ______

- (activation of) immune cells

Step 3. remodeling of airway tissue

Pathologic cascade of asthma

step 2. activation of immune cells

step 3. ___________________ of airway tissue

- remodeling (of airway tissue)

step 4. hypercontractile status

Pathologic cascade of asthma

step 3. remodeling of airway tissue

step 4. _____________ status

- hypercontractile (status)

Structural changes in the asthmatic pathway

Asthmatic airways have:

1. Increased number of goblet cells

(mucus production)

2. Thickened basement membrane

(myofibroblasts, extracellular matrix)

3. Increased number of smooth muscle

cells (hyperplasia)

4. Increased size of smooth muscle

cells (hypertrophy)

Structural changes in the asthmatic pathway - asthmatic airways have: increased number of ____________ _______, which _______ mucus production

- (increased number of) goblet cells

- increase (mucus production)

Structural changes in the asthmatic pathway - asthmatic airways have: thickened _____________ ________

- basement membrane

Myofibroblasts, extracellular matrix

Structural changes in the asthmatic pathway - asthmatic airways have: increased number of _________ _________ cells (__________)

- smooth muscle (cells)

- hyperplasia

i.e., increased amount of smooth muscle cells

Structural changes in the asthmatic pathway - asthmatic airways have: increased size of smooth muscle cells (_________)

- hypertrophy

i.e., strengthening of these smooth muscles

Bronchoconstriction is a ___________ physiologic response

- normal (physiologic response)

Non-asthmatics: low-level response to stimulus that produces mild, if any, bronchonstriction at normal to high doses (normal response)

Asthmatics are ALWAYs hyper-responsive airways

Bronchoconstriction normal physiological response: non-asthmatics

low-level response to stimulus that produces mild, if any, bronchoconstriction at normal to high doses

see figure 1a

Bronchoconstriction normal physiological response: Asthmatics ALWAYs have _______-_________ airways

- hyper-responsive (airways)

hypersensitivity: normal response to abnormally low stimulus dose (leftward shift)

hyperreactivity: exaggerated response to normal-high stimulus dose (upward shift)

see figure 1a

Insults

events in the brain such as trauma, infection, or chemical imbalance

Bronchoconstriction figure 1a

Non-asthmatics:

low-level response to stimulus that produces mild, if any, bronchonstriction at normal to high doses (normal response)

Asthmatics: hypersensitivity: normal response to abnormally low stimulus dose (leftward shift)

hyperreactivity: exaggerated response to normal-high stimulus dose (upward shift)

Methacholine challenge diagnosis: inhale _____________ concentrations of methacholine aerosols with ________ before and after each dose

- (inhale) increasing (concentrations of methacholine)

- spirometry

Results recorded as percent decrease in FEV1 from baseline for each step of the protocol & concentration applied

Methacholine challenge diagnosis: Results recorded as __________ decrease in ______ from baseline for each step of the protocol & concentration applied

- percent (decrease)

- FEV1

Positive reaction = 20% fall in FEV1

Methacholine challenge diagnosis: positive reaction = ___% fall in FEV1

- 20(% fall in FEV1)

If FEV1 does not fall by at least 20% the test is negative

Methacholine challenge diagnosis: negative reaction; does ______ fall by at __________ ___%

- NOT (fall)

- (at) least 20(%)

Methacholine challenge diagnosis: ____________ methacholine concentration varies by institution

- maximum (methacholine concentration)

Early asthma attack: bronchospasm - allergen attaches to _______ ________ and immunoglobulin-____ releases __________

- mast cell

- (immunoglobulin-)E

- (releases) histamine

Which causes the bronchospasm of the smooth muscle airway

Allergen also alerts the T-lymphocyte

Early asthma attack: allergen also alerts the ____-___________ which leads to the release of many __________

- T-lymphocytes

- (many) cytokines

IL-4, IL-5, GM-CSF, TNF, TGF

Cytokines released by t-lymphocytes after exposure to allergen induced asthma

IL-4

IL-5

GM-CSF

TNF

TGF

Cytokines from the t-lympocytes lead to late stage ___________

- (late stage) inflammation

Eosinophil releases ECP + MBP; Neutrophils release proteases + PAF

ECP

eosinophil cationic protein

MBP

major basic protein

Eosinophils release _____ and _____ during asthma

- ECF

- MBP

Neutrophils release _______ and _____ during asthma

- proteases

- PAF

Airway smooth muscle is innervated by the ______________ nervous system ONLY

- parasympathetic (nervous system ONLY)

Airway smooth muscle contraction pathway

Ach -> M3AchR activates Phospholipase C -> PIP2 -> IP3 +DAG

DAG pathway

PKC (protein kinase C) -> contraction

IP3 pathway

IP3 increase of Ca in the seroplasmic reticulum, increased Ca2+ -> contraction

Airway smooth muscle contraction pathway: IP3 pathway

IP3 increase of Ca in the seroplasmic reticulum -> increased intracellular Ca2+ -> contraction

Airway smooth muscle contraction pathway: DAG pathway

DAG -> PKC (protein kinase C) -> contraction

Airway smooth muscle contraction pathway: early pathway in order to get DAG + IP3

Ach -> M3AchR activates Phospholipase C -> PIP2 -> IP3 +DAG

Muscarinic receptors in lung - submucosal glands

M1 and M3

Bronchial secretions

Muscarinic receptors in lung - airway smooth muscle

M3 and M2

bronchoconstriction

Muscarinic receptors in the lung - autoreceptors

M2

M2 are the auto receptors that signal the stop to the M1 and M3 in the submucosal glands and the M2 and M3 in the airway smooth muscle

autoreceptors

signal the presynaptic neuron to stop releasing the neurotransmitter

Airway smooth muscle relaxation is primarily driven by _______________ ___________

- circulating epinephrine

Airway smooth muscle innervation (parasympathetic) figure

Airway smooth muscle relaxation figure

Phosphokinase C from DAG in airway smooth muscle innervation / contraction leads to ______________ and __________

- hypertrophy

- (and) hyperplasia

Airway smooth muscle relaxation pathway

Epi -> β2AR -> GS -> adenylate cyclase -> ATP to cAMP -> inhibits contraction (fast response)

Epi -> β2AR -> hypertrophy (slow response); thus the use of β2-agonists long-term still causes hypertrophy despite use of rescue of asthma (not good in the long-run)

Airway smooth muscle relaxation pathway: fast response

Epi -> β2AR -> Gs -> adenylate cyclase -> ATP to cAMP -> inhibits contraction

cAMP via PDE -> AMP

Thus relaxation

Airway smooth muscle relaxation pathway: slow response

Epi -> β2AR -> hypertrophy (slow response)

The use of β2-agonists long-term still causes hypertrophy despite use of rescue of asthma (not good in the long-run)

Yin/Yang control of bronchial tone - cholinergic action: cholinergic (_____) receptors located in large bronchioles due to _________ innervation.

This causes ___________

- M3

- vagal (innervation)

- bronchoconstriction

Yin/Yang control of bronchial tone - cholinergic action: acetylcholine innervates M2 receptors and ________________ adenylate cyclase (AC) to ___________ bronchodilation

- inhibits (adenylate cyclase)

- prevent (bronchodilator)

i.e., M3 causes bronchoconstrction; M2 prevents bronchodilation

Yin/Yang control of bronchial tone - adrenergic action: β2 receptors located in _________ bronchioles: ___ ________ innervation; only stimulated by __________ epinephrine

- small (bronchioles)

- no direct (innervation)

- circulating (epinephrine)

Regularly follow-up asthmatic patients every ____ __________

- (every) 3 months

Yin/Yang Control of Bronchial Tone Figure

Asthmatics lose the ____________ between the bronchial tone

- (lose the) balance

Bronchoconstriction is more sensitive

Asthma mechanisms: _____ and ________ _________; Mast cell _______ in exacerbations

- IgE

- mast cells

- mediates (in exacerbations)

Asthma mechanisms: Th2 Inflammatory cytokines in asthma

IL-4

IL-5

IL-13

Asthma mechanisms: basophil

FceRI

FceRI

receptor present in the surface of mast cells, basophils, and activated eosinophils that binds free IgE with very high affinity. When antigen binds to IgE and cross-links FcERI, it causes cellular activation and degranulation

Environment and gene involvement in asthma: _____________ _________ slightly after birth, which may lead to ________ _____________ and _________ development

- maternal exposure

- lung morphogenesis

- immune (development)

KR is now 19 years old and has had a history of asthma for 3 years. She is generally well controlled but has significant flare ups during soccer season and also in the Spring when flowers are blooming. This year, she had a severe upper respiratory tract infection and her recovery time took 2 weeks due to significant wheezing and worsening of her asthma. Previously, she was able to control her asthma quite well when she avoided triggers and could go over a year without any attacks.

What are some respiratory tract changes that KR is experiencing?

Inflammation - increase inflammatory mediators

Increase mucus from the goblet cells

Hypertrophy and hyperplasia of bronchiolar smooth muscles

KR is now 19 years old and has had a history of asthma for 3 years. She is generally well controlled but has significant flare ups during soccer season and also in the Spring when flowers are blooming. This year, she had a severe upper respiratory tract infection and her recovery time took 2 weeks due to significant wheezing and worsening of her asthma. Previously, she was able to control her asthma quite well when she avoided triggers and could go over a year without any attacks.

How would these changes lead to worsening of chronic asthma?

Hypertrophy and hyperplasia occurs due to bronchoconstriction, which leads to a larger and stronger response

Bronchiolar smooth muscle hypertrophy is signaled by _____________ __________ ______

- protein kinase C

DAG

diacylglycerol

Histamine acts similar to _______________ ______ in the activation of asthma

- (similar to) acetylcholine M3

Histamine from Mast Cells triggers PKC and Ca2+ -> bronchoconstrction