Lecture 2 - Asthma pathology

Question 1

what is the pathogenesis of asthma?

Answer 1

cough, wheeze or chest tightness at night or in the morning after exposure to a variety of environmental stimuli

Question 2

what are environmental stimuli?

Answer 2

hyper-responsive to the constrictor effects of a stimuli such as:

exercise - non specific

cold air - non specific

hyperventilation - non specific

chemical agents - non specific

allergens - specific to asthmatics that respond to allergies

aspirin - only specific to those patients that display hyper responsiveness to aspirin

Question 3

what are the 5 characteristics of asthma ?

Answer 3

1. inflammatory response - eosinophils, mast cells or neutrophils
2. hyper-responsiveness of smooth muscle to substances that cause contraction of the smooth muscle, such as acetylcholine, histamine, and PAF
3. hypo-reposnsiveness of the smooth muscle to substances that relax smooth muscle, such as adrenaline
4. neuronal imbalance
5. hyperplasia and hypertrophy

Question 4

what are the airway changes in asthma?

Answer 4

bronchospasm

lining swells

mucus increases

bronchiole constriction

muscle constriction

Question 5

what is the morphology of bronchitis asthma gross?

Answer 5

lungs are over distended due to over-inflation

small areas of atelectasis (collapse of parts or commonly all of lung) can be seen

occlusion of bronchi and bronchioles by thick tenacious mucous plug - most striking finding.

Question 6

what is present in the airways ?

Answer 6

numerous eosinophils are present and lysophospholipase D crystallises in the airway lumen

Question 7

what are the structural changes remodelling in airways of asthma?

Answer 7

epithelial damage, mucosal oedema, increased intraluminal secretions, basement membrane thickening, smooth muscle hypertrophy and hyperplasia and inflammation

Question 8

what are the proposals for the alteration in smooth muscle contractility?

Answer 8

increased mediator and cytokine induced contraction

alteration in calcium control and contraction/ relaxation

proliferative response increases muscle mass and increase force of contraction

Question 9

describe changes that happens to the airway smooth muscles and how they are affected in asthma

Answer 9

Increased number of cytokines- so it contracts more

Take muscle from chronic asthma patients it contracts more to methacholine- Hyperresponsive (something intrinsic)

More stiffness- lack of breathing induced muscle softening (think deep breathing)

Increased muscle mass- increased force of contraction

Can release cytokines (autocrine/paracrine)

Question 10

what does contraction of M3 muscarinic receptors on airway smooth muscle do?

Answer 10

activation of M3 msucarinci receptors which couple to Gq initiates contraction of airway smooth muscles

Question 11

what happens to the amounts of Rho in asthma ?

Answer 11

higher amounts of Rho kinase due to cytokine mediated gene induction - more sustained contraction

Question 12

what is the autonomic imbalance in asthmatics?

Answer 12

there is reduced adrenergic beta-adrenoreceptors and there is an increased cholinergic acetylcholine release - stimulated by tachykinins, 5-HT, TAXA2

Question 13

what does the increased cholinergic release?

Answer 13

release acetylcholine that is a powerful bronchoconstrictor - this underlies the hyper-responsiveness of the smooth muscle in the bronchial tree

Question 14

what do adrenergic control influence and what do inflammatory mediators do to adrenergic control?

Answer 14

adrenergic control influence cholinergic control

inflammatory mediators such as histamine can modulate adrenergic control. for example, cytokines (TNFa) reduces beta 2 adrenoreceptor responsiveness.

Question 15

what does release of acetylcholine trigger and what do afferent substances respond to?

Answer 15

the release of acetylcholine triggers contraction of smooth muscle. Afferent nerves, e.g. C-fibres respond to substances, such as histamine, bradykinin, prostaglandins to cause a reflex bronchoconstriction.

Question 16

what are the defects in cholinergic innervation?

Answer 16

(a) increased vagal tone.

(b) reflex bronchoconstriction.

(c) increased acetylcholine release: Adrenergic nerves inhibit acetylcholine release, suggesting defects in b- or a2 receptor function.

(d) increased post-synaptic muscarinic receptor function

Question 17

what do the adrenergic nerves release?

Answer 17

adrenergic nerve releases nor-adrenaline that inhibits the cholinergic nerve to reduce acetylcholine release leading to bronchodilation

Question 18

what do C fibres in the airway respond to?

Answer 18

C fibres in the airway epithelium which response to inflammatory mediators to produce a reflex activation of the cholinergic nerve leading to bronchoconstriction

Question 19

what are defective NANC inhibitory nerves and what do they cause?

Answer 19

relaxation

These include VIPergic nerves and Nitric oxide release which are the only neural innervation that elicits bronchodilation (not much evidence in asthma).

Question 20

what do increased NANC excitatory nerves cause and release?

Answer 20

constriction

Release of substance P and neurokinins from a subset of C-fibre sensory nerve endings. This occurs in response to prostaglandins and bradykinin released as a consequence of inflammation.

Question 21

what do defective NANC inhibitory nerves and increased NANC excitatory nerves cause?

Answer 21

this causes a reflex bronchocontriction, hyperaemia, mciroascualr leakage and hyper section. local reflex may among

Question 22

describe airway muscle proliferation

Answer 22

Both hypertrophy (cell size) and hyperplasia (cell number) involved

Stimulated by multiple growth factors and mediators produced which cause proliferation

Can release its own mediators- autocrine loop and effect on other cells

Bronchial biopsies from patients proliferate more

Associated with hyper responsiveness and increased stiffness- important in severe asthma

Question 23

when does the proliferation response occur in? what elicits it?

Answer 23

The proliferative response occurs in chronic asthmatics. Growth factors elicit mitogenesis and cell proliferation. This involves a complex signalling pathway involving growth factors.

Question 24

what activates the proliferation response pathway ?

Answer 24

Bronchoconstrictors can activate this pathway at several points including raf-1 kinase and MAP kinase.

Question 25

describe how T cells are activated to produce TH2 cells and causes bronchoconstriction

Answer 25

Allergens such as dust mites is processed by dendritic ells in MHCIII complex, and presents to T cells which are activated and transformed into TH2 cells.

the TH2 cells cause immature B cells to produce antibodies that recognise the original pollen. IgE is released from B cells and binds to receptors on mast cells, to release inflammatory mediators to such as tachykinins and leukotrienes - causing bronchoconstriction. these factors also activate C-fibre to cause bronchosocntriction.

TH2 cells also promote recruitment of eosinophils into the airway. the recruitment of eosinophils into the airway causes release of free radicle which cause epithelium damage in the airway and promote hyperplasia/hypertrophy of the smooth smuggle in an amplification cascade ty hyper-reactivity (asthma)

Question 26

what is the early phase of ifnalmamtory response?

Answer 26

early phase: This is where the inflammatory cells are
recruited to sites in the pulmonary arteries and enter into
the interstitial fluid and smooth muscle by squeezing
through the endothelium, an event called diapedesis

Question 27

what is the late phase of the inflammatory response

Answer 27

late phase: This is where the inflammatory cells attach to
the epithelium and squeeze through the lining into the
airway tubule. The release of substances such as O2.,
major basic protein and PAF have a potent killing effect
upon the epithelial cells and extensive damage to the
epithelial lining is achieved.