Lecture 2 - Asthma pathology Flashcards
what is the pathogenesis of asthma?
cough, wheeze or chest tightness at night or in the morning after exposure to a variety of environmental stimuli
what are environmental stimuli?
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
what are the 5 characteristics of asthma ?
- inflammatory response - eosinophils, mast cells or neutrophils
- hyper-responsiveness of smooth muscle to substances that cause contraction of the smooth muscle, such as acetylcholine, histamine, and PAF
- hypo-reposnsiveness of the smooth muscle to substances that relax smooth muscle, such as adrenaline
- neuronal imbalance
- hyperplasia and hypertrophy
what are the airway changes in asthma?
bronchospasm
lining swells
mucus increases
bronchiole constriction
muscle constriction
what is the morphology of bronchitis asthma gross?
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.
what is present in the airways ?
numerous eosinophils are present and lysophospholipase D crystallises in the airway lumen
what are the structural changes remodelling in airways of asthma?
epithelial damage, mucosal oedema, increased intraluminal secretions, basement membrane thickening, smooth muscle hypertrophy and hyperplasia and inflammation
what are the proposals for the alteration in smooth muscle contractility?
increased mediator and cytokine induced contraction
alteration in calcium control and contraction/ relaxation
proliferative response increases muscle mass and increase force of contraction
describe changes that happens to the airway smooth muscles and how they are affected in asthma
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)
what does contraction of M3 muscarinic receptors on airway smooth muscle do?
activation of M3 msucarinci receptors which couple to Gq initiates contraction of airway smooth muscles
what happens to the amounts of Rho in asthma ?
higher amounts of Rho kinase due to cytokine mediated gene induction - more sustained contraction
what is the autonomic imbalance in asthmatics?
there is reduced adrenergic beta-adrenoreceptors and there is an increased cholinergic acetylcholine release - stimulated by tachykinins, 5-HT, TAXA2
what does the increased cholinergic release?
release acetylcholine that is a powerful bronchoconstrictor - this underlies the hyper-responsiveness of the smooth muscle in the bronchial tree
what do adrenergic control influence and what do inflammatory mediators do to adrenergic control?
adrenergic control influence cholinergic control
inflammatory mediators such as histamine can modulate adrenergic control. for example, cytokines (TNFa) reduces beta 2 adrenoreceptor responsiveness.
what does release of acetylcholine trigger and what do afferent substances respond to?
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.
what are the defects in cholinergic innervation?
(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
what do the adrenergic nerves release?
adrenergic nerve releases nor-adrenaline that inhibits the cholinergic nerve to reduce acetylcholine release leading to bronchodilation
what do C fibres in the airway respond to?
C fibres in the airway epithelium which response to inflammatory mediators to produce a reflex activation of the cholinergic nerve leading to bronchoconstriction
what are defective NANC inhibitory nerves and what do they cause?
relaxation
These include VIPergic nerves and Nitric oxide release which are the only neural innervation that elicits bronchodilation (not much evidence in asthma).
what do increased NANC excitatory nerves cause and release?
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.
what do defective NANC inhibitory nerves and increased NANC excitatory nerves cause?
this causes a reflex bronchocontriction, hyperaemia, mciroascualr leakage and hyper section. local reflex may among
describe airway muscle proliferation
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
when does the proliferation response occur in? what elicits it?
The proliferative response occurs in chronic asthmatics. Growth factors elicit mitogenesis and cell proliferation. This involves a complex signalling pathway involving growth factors.
what activates the proliferation response pathway ?
Bronchoconstrictors can activate this pathway at several points including raf-1 kinase and MAP kinase.
describe how T cells are activated to produce TH2 cells and causes bronchoconstriction
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)
what is the early phase of ifnalmamtory response?
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
what is the late phase of the inflammatory response
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.
