MW L1 Asthma introduction Flashcards
What percentages of deaths from asthma are preventable?
90%
Definition of asthma
chronic inflammatory condition of the airways,
- associated with VARIABLE airway obstruction
- increase in airway response to variety of stimuli
Asthma is associated with …… airway obstruction which is often ………..
variable reversible (with treatment of spontaneously)
PEFR is
peak expiratory flow rate
blow as fast as you can into the tube
FEV1 is
forced expiratory volume
integrates the PEFR over 1 second
Lung function test eg (2)
PEFR and FEV1
What does lung funct measure
They are both measures of EXPRIRATION
Asthmatics have trouble with them. Expiration is usually a passive process.
Step 1 Asthma attack
Early bronchoconstriction
Over mins - hours function falls.
Largely due to contraction of smooth muscle.
Step 2 Asthma attack
Pt feels fine for some hours.
Step 3 Asthma attack
Hours later wheezing occurs, associated with inflammation.
Oedema.
Interstitial connective tissue becomes spongy.
Excess secretions.
Which part of an asthma attack is caused by bronchoconsriction and which by oedema, secretion and inflammation
Bronchoconstriction - early stage
Oedema, secretions and inflammation - late stage
Asthma patients show increased ……(2)……… when exposed to something causing brconchoconstriciton
Increased maximum response and sensitivity
compared to healthy person
4 mechanisms of hyperresponsiveness
1 Increased smooth muscle contractility
2 Increased excitatory nerve actitivty
3 Decreased bronchililator activity
4 Inflammation
Mechanism of hyperresponsiveness:
1. Increased smooth muscle contractility
What happens? (2)
Hyperplasia & hypertrophy
- therefore muscles contract more
Mechanism of hyperresponsiveness:
1. Increased smooth muscle contractility
Hyperplasia means
more muscle cells
-this means they can develop tension and constrict harder
Mechanism of hyperresponsiveness:
1. Increased smooth muscle contractility
Hypertrophy means
bigger muscle cells
Mechanism of hyperresponsiveness:
1. Increased smooth muscle contractility
Smooth muscle growth regulators (2 main categories):
Mitogens (cause cell growth) and modulators (switch off growth)
Mechanism of hyperresponsiveness:
1. Increased smooth muscle contractility
4 examples of mitogens
Platelet derived growth factor Endothelin Cytokines Histamine (cells growth happens over weeks and months not just hours)
Mechanism of hyperresponsiveness:
1. Increased smooth muscle contractility
3 examples of modulators
Heparin
Nitric oxide
Prostaglandin E2
(switch off smooth muscle growth so may be beneficial)
Mechanism of hyperresponsiveness:
2 Increased excitatory nerve actitivty
Airway is innervated by which nerves?
The vagus
Mechanism of hyperresponsiveness:
2 Increased excitatory nerve actitivty
What type of nerves innervate the airways?
(….. acting on …. receptors)
Cholingergic
ACh acting on M3 receptors
Mechanism of hyperresponsiveness:
2 Increased excitatory nerve actitivty
Appart from ACh what other neurotransmitters cause contractile response
Excitatory non-adrenergic non-cholinergic transmitters (eNANC)
Mechanism of hyperresponsiveness:
2 Increased excitatory nerve actitivty
eNANC acts on
neurokinin receptors, (these are peptides)
Mechanism of hyperresponsiveness:
2 Increased excitatory nerve actitivty
3 examples of eNANC
substance P
neurokinin A
neurokinin B
Mechanism of hyperresponsiveness:
2 Increased excitatory nerve actitivty
Both Cholinergic nerves and eNANC stimulate…….. causing bronchiconstriction
stimulate GPCR leading to elevation of intracellular free Ca
Mechanism of hyperresponsiveness:
2 Increased excitatory nerve actitivty
How do cholinergic nerves cause bronchoconstriction?
release ACh, acts on M3 receptors (Gq)
PLC hydrolysis membrane IP3
Intracellular Ca released into cytoplasm
Mechanism of hyperresponsiveness:
2 Increased excitatory nerve actitivty
How does increased Ca cause bronchoconstriction?
Ca binds to calmodulin and activates MLCK - causes contraciton
(myosin light chain kinase)
What does myosin light chain kinase do?
phosphorlylates MLC to MLC-P
MLC-P causes contraction
Mechanism of hyperresponsiveness:
2 Increased excitatory nerve actitivty
Negative feedback system for ACh causing smooth muscle contraction?
ACh acts back on M2 receptors in the parasympathetic nerve terminal.
M2 reduces the levels of ACh being released.
Mechanism of hyperresponsiveness:
3 Decreased bronchililator activity
Main categories of bronchodilators (2)
- Circulating adrenaline
- Inhibitory non-adrenergic non-cholinergic transmitters (iNANC)
Mechanism of hyperresponsiveness:
3 Decreased bronchililator activity
How does circulating adrenaline cause bronchodilation?
acts on beta-adrenoreceptors on airway smooth muscle
There are more para or symp nerves in the airways?
Parasympathetic. - causing constriciton
most dilation comes from adrenaline
Mechanism of hyperresponsiveness:
3 Decreased bronchililator activity
Two main iNANC?
Neuronally-derived NO
Dilator neuropeptides
Neuronally derived NO acts on… to cause…
soluble guanylate cyclase to cause bronchodilation
name 2 dilator neuropeptides
act on…. to cause….
CGRP (calcitonin-gene related peptide)
VIP (vasoactive intestinal polypeptide)
activate adenylyl cyclase to cause bronchodilation
Mechanism of hyperresponsiveness:
3 Decreased bronchililator activity
Main’classical’ pathway that beta2 adrenoreceptor activation causes bronchodilation?
activaition causes GPCR to convert ATP into cAMP.
cAMP activates PKA.
PKA inactivates MLCK.
Mechanism of hyperresponsiveness:
3 Decreased bronchililator activity
Beta2 adrenoreceptors activates PKA. How can PKA cause bronchodilation? (3) + (1)
- inactivates MLCK (‘classical’ pathway)
- opens K+ channels, becomes hyperpolarised and harder to electrically activate
- Calcium sequestration
-Beta2 also activates MLC phosphotase
Mechanism of hyperresponsiveness: 4 Inflammation Main mechanisms (2)
- epithelial damage and exposure of sensory nerves
- oedema leading to decreased luminal diameter
Why is mucus white?
lots of WBC
severe asthma what becomes a problem?
scarring of the airway
5 Evolving concepts in asthma pathogenisis?
- primary abnormality of airway-myocyte hyperresponsiveness
2 autonomic dysfuntion with exagerated activity of chilinergic or tacykinnin pathways - IgE mediated mast cell/ basophil degranulation
- Complex T lymphocyte mediated airway inflammation
- airway remodelling
