Lecture 2: The pathology of Asthma 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 the airways of asthmatic patients like?
Hyper-responsive to the constrictor effects of a number of stimuli
What are the specific stimuli that trigger asthma?
- Aspirin
- allergens
What are the non specific stimuli that trigger asthma?
- Exercise
- Cold air
- Hyperventilation
- Chemical agents
How does cold air breathing lead to asthma through heat loss?
- Breathe cold air
- Heat loss
- Mucosal cooling
- Sensorineural activation
- Changes in epithelial ion transport
- Increased blood flow
- Venous ebgorgement
- Increased glandular activity
What are the characteristics of asthma?
- Inflammatory cells involved are eosinophils, mast cells and neutrophils
- Smooth muscle is hyper responsive to substances that cause contraction such as acetylcholine, histamine and PAF
- Smooth muscle is hypresponsibe to substances that cause relaxation such as adrenaline
- Neuronal imbalance - increase in parasympathetic activity and decreased sympathetic activity
- Remodelling of airways - hyperplasia and hypertrophy
What is the predominant cell in asthmas?
Eosinophil
What does the inflammatory response result in?
- Causes the release of inflammatory mediators
- They can activate sensory C fibres in the epithelial layer of the airway
- This can cause a reflex bronchoconstriction, making it difficult for the patient to breathe
What is acetylecholine released by?
Parasympathetic nerve
What causes bronchoconstriction in the airway?
- Acetylecholine
- Histamine
- Platelet aggregating factor
What substances are smooth muscles hyperresponsive too?
- Aceytlecholine
- Histamine
- Platelet agregating factor
What substances are smooth muscles hyporresponsive too?
Adrenaline
What causes relaxation of smooth muscles?
Adrenaline
What are the three major nerve control mechanisms in the airway?
- Parasympathetic nerve releases acetylecholine to cause bronchoconstriction
- Adrenergic nerves releases noradrenaline - this inhibits the release of acetylecholine from the parasympathetic nerve so causes bronchodilation
- Non adrenergic nerves: actiavted in the epithelium through C fibre stimulation by inflammatory mediators - they can cause excitary and inhibitory responses (bronchodilation and bronchoconstriction)
What is hyperplasia?
Cells divide causes engorgement of tissue
What is hypertrophy?
Increase and growth of cells
What are the changes in the airways in an asthmatic patient?
- Layer of the smooth muscle contracts causing bronchoconstriction - narrowing of airway lumen
- Damage, hypertrophy swelling of epithelial lining
- Enhanced activity of goblet cells - secrete mucus in response to inflammation
What is mucosal odema?
Formation of mucus plug in the airway
What is the basement membrane?
The layer upon which the epithelial cells sit
What are the morphological changes in bronchitial asthma?
- Lungs are over distended due to over inflamation
- Small areas of atelectasis (lung collapse) can be seen
- Occlusion of bronchi and bronchioles by thick tenacious mucous plug
What is the lavage?
Fluid from the airway of asthmatics
What would you find in the mucus from the airways of an asthmatic?
- Full of eosinophils due to thier infiltration
- Charcot-Leyden crystals
What are Charcot-Leyden crystals?
Crystals of the enzyme-Lysophospholipase D which crystalizes in the airway lumen.
What is an easy marker of whether a pateint has asthma?
Charcot-Leyden crystals
How are smooth muscle cells innervated?
Each cell is innervated from a single neuron from the parasympathetic nerve. The parasympathetic nerve releases acetylecholine, it binds to muscarinic receptor on the smooth muscle cell and cuases depolarization - this results in contraction
What is a gap junction?
A tiny pore between cells formed by a protein called conexin 43.
How does calcium enter cells?
- Via voltage and receptor operated calcium channels
- From sarcoplasmic reticulum stores
How does acytylecholine induce contraction in smooth muscle leading to bronchoconstriction?
- Aceytylecholine binds to muscarinic 3 receptor uses the G protein Gq to activate an enzyme called phospholipase C
- This enzyme catylyses the hydrolysis PIP2, to produce second messengers IP3 and DAG
- DAG remains in the plasma membrane and activates the enzyme protein kinase C that catylyses the phosphorylation of …
What is enhanced hyperplasisa?
- A proliferative response where smooth muscel cells dedifferentiate into myofibroblasts, they can then enter the cell cycle to undergo mitosis to increase the muscel mass in the airway of asthmatics
- Occurs in chronic asthmatics
- The process of mitogensis is activated by growth factors - the levels of these growth factors are increased in asthmatics
- It involves a complex signalling pathway that results in the activation of MAP kinase
What are typical bronchoconstrictors?
- Aceytylcholine
- Leukotriene D4
What can activate MAP kinase?
- Growth factors
- Regular G protein coupled receptor agonists
What is the autonomic imbalance in asthmatics?
- The adrenergic nervous system is down regulated: may be a consequence of reduced beta adrenoreceptors expressed in the bronchial smooth muscle
- Enhances release of acetylecholine from cholonergic nerve leading to an imbalance in the bronchodilateion vs bronchoconstriction responses - this is stimulated by tackykinins
Why is the magnitude of reposnses of beta 2 agonists reduced?
Compromised by the fact the receptors are reduced in number in bronchial smooth muscle
What does the cholinergic nerve release?
Acetylcholine
How does acetylcholine affect smooth muscle?
Causes contraction
What do afferent receptors respond to?
- histamine
- bradykinin - prostaglandins to cause a refelx of bronchoconstruction
What are the defects in cholinergic innervation in asthmatic patients?
- Increased vagal tone
- Reflex bronchonconstriction due to activation of sensory C fibres
- Increased acetylcholine release: increaesd neurotransmission that is facilitated by tackykinins, thromboxanes and serotonin. Adrenergic nerves inhibit acetylcholine release
- Increased post synaptic muscarinic receptor
What is the function of adrenergic control?
Influence cholinergic control
What controls non adrerergic non cholinergic (NANC) transmission?
Excitarory and inhibitory nerves
What are the two phases on the inflammatory response?
- Early phase
- Late phase
What is the 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?
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.
What are the inflammotry cells involved in the process?
- Mast cells: these cells respond to allergen and IgE by releasing histamine, TNFa, LTD4, and various interleukins such as IL1.
- Neutrophils and basophils
- Macrophage: these cells release prostanoids, cytokines and leukotrienes.
- Eosinophils: these cells release PAF, TNFa, O2,eotaxin, IL-4, IL-5, CSF (which causes haematopoetic stem cells to differentiate
into progenitor cells), GMSCF (which causes progenitor cell to differentiate into eosinophils) and MBP.
How do C fibres have an effect in asthma patients?
- Irritants such as smoking, cold air activate irritant receptors
- These activate c fibre receptors
- C fibres have an effect on parasympathetic ganglia
- Cause acetylcholine release and act on smooth muscle cells to cause bronchonstriction
- Ach also acts on submucosal gland to increase mucus release
Why do NSAIDS not work for asthma?
Reduce PGE2 and PGF2 alpha and TXA2 in the lung. May also redirect activation of the leukotriene pathway which is contractile
What reduces beta 2 adrenoceptor responsiveness.
Cytokines - TNFa
What do NANC inhibitory nerves release?
VIPergic nerves and Nitric oxide
What does defective NANC inhibitory nerves cause
Relaxation
What do increased NANC excitatory nerves cause?
Constriction
What do NANC excitatory nerves release?
substance P and neurokinins in response to prostaglandins and bradykinin released as a consequence of inflammation.
