Block D - asthma Flashcards
name 2 respiratory diseases ?
asthma and COPD
asthma ?
inflammatory disease
COPD ?
aberrant wound healing diseases (fibrosis) response that involves inflammatory cells.
why does inflammation occur in asthma ?
Inflammatory response mediated by eosinophils, mast cells and neutrophils. These infiltrate into the airways from the blood. In asthma the predominate cell is eosinophil
inflammation in COPD ?
Inflammatory response mediated by eosinophils, mast cells and neutrophils. These infiltrate into the airways from the blood. In COPD the predominate cell is neutrophils.
hyper responsiveness in asthma ?
In asthma Hyperresponsiveness of smooth muscle to substances that cause contraction of the smooth muscle in the airways (bronchoconstriction), such as acetylcholine, histamine and PAF. Bronchoconstriction makes it harder to breathe.
hypo responsiveness in smooth muscle ?
Hypo responsiveness of the smooth muscle to substances that relax smooth muscle (bronchodilation), such as adrenaline. Need a smaller amount of adrenaline compared to healthy patients.
neuronal imbalance ?
Neuronal imbalance in asthmatics, 3 major nerve controls in the airways: parasympathetic releasing Ach for bronchoconstriction, adrenergic releases noradrenaline to inhibit Ach release (tilt system for bronchodilation), non-adrenergic nerves activated in epithelial by C fibres by inflammatory mediators these can causes excitation responses including bronchoconstriction and inhibitory responses such as bronchodilation.
hyperplasia and hypertrophy in asthma ?
Hyperplasia and hypertrophy, the smooth muscle itself can dedifferentiate into myofibroblasts that are then able to divide and increase the muscle mass, this is called hyperplasia. The smooth muscle can change phenotypically into synthetic smooth muscle cells so they are more likely to release inflammatory mediators this is called hypertrophy.
remodelling ?
The smooth muscle in the airway can undergo remodelling, it increases in muscle mass and synthetic capability for a site of inflammatory mediators so that bronchoconstriction is increased and the symptoms of asthma.
airways in asthma ?
In asthmatics the bronchial smooth muscle cells contract to narrow the airway lumen, making it harder to breath. The smooth muscle undergoes proliferation (hyperplasia) and the cells enlarge (hypertrophy) and as well as contracting become ‘synthetic’ (produce inflammatory mediators that can cause contraction of the smooth muscle-bronchoconstriction).The goblet cells also produce excessive mucus secretion (oedema) in asthmatics that cause an obstructive plug, making it more difficult to breath
current proposal for alteration of smooth muscle excitability ?
There are three current proposals for the alteration in smooth muscle excitability. These are:
(i) abnormalities in conduction properties.
(ii) alteration in calcium control and contraction/ relaxation
(iii) proliferative response increases ( hyperplasia)
morphology of bronchial asthma ?
lungs are over-distended due to over-inflation
small areas of atelectasis ( lung collapse) can be seen
occlusion of bronchi and bronchioles by thick tenacious mucous plug (odema):- most striking finding.
lavage fluid ?
The lavage (fluid) from the airway lumen of asthmatics contains many eosinophils (this is the primary cell involved in asthma, and which can communicate with other inflammatory cells to amplify the inflammatory response).
charcot’Leyden crystals ?
Charcot-Leyden crystals are made of an enzyme-Lysophospholipase D which is released from airway cells into the mucus plug and it crystalizes in the airway lumen. They are an easy marker of whether a patient has asthma.
conduction properties ?
Generally, the smooth muscle is considered as being multi-unit type, i.e each smooth muscle cell is innervated and cell to cell communication is poor, e.g. few gap junctions through which electrical signals can pass with low resistance. In asthmatics the cells become single unit in nature and there is an increased occurrence of gap junctions as asthmatics there is an upregulation of the connexin 43 gene so more is expressed and more gap junctions’ form. The parasympathetic nerve is activated it releases acetylcholine which binds to the muscarinic receptor on smooth muscle cell, depolarisation occurs, and electrical stimuli passes from one cell to another cell to cause contraction. In asthmatics instead of one cell activating another cell, activation of one cell causes many other cells to also be activated. This can lead to hyper responsiveness of the muscle cells in asmathics.
how can calcium eneter cells ?
(I) via voltage- and receptor-operated calcium channels – calcium channel that open when the threshold reaches a certain level during depolarisation and calcium channels are opened so that calcium can flow into a cell causing contraction and bronchoconstriction.
(ii) from sarcoplasmic reticulum stores - phospholipase C is associated with M3 receptors, these release intracellular stores of calcium as it flows from an area of high concentration the SR to an area of lower concentration the cytoplasm, this initiates contraction and bronchoconstriction.
bronchoconstricotors such as Ach ?
Bronchoconstrictors, such as acetylcholine bind to the receptor. This leads to the activation of Gq in M3 receptors which in turn stimulates the enzyme, phospholipase C. PLC catalyses the conversion of the phospholipid Ptd(Ins)4,5P2 into diacylglycerol (activates PKC that phosphorylates proteins( PKC) involved in contraction to sustain this response-latch bridge) and Ins(1,4,5)P3, which diffuses into the cytoplasm. When it reaches the SR, it binds to the Ins(1,4,5)P3 receptor, which is a receptor calcium channel. This results in opening of the channel and calcium flows from a high concentration (in the SR) into the cytoplasm. Here, it combines with calmodulin and this complex activates myosin light chain kinase, an enzyme that transfers phosphate from ATP on myosin light chain. Once phosphorylated myosin light chain can bind to actin to cause the contraction.
what do asthmatics have increased in smooth muscle ?
In asthmatics this leads to bronchoconstriction. Asthmatics may well have increased Ins(1,4., 5)P3 receptors expressed in their bronchial smooth muscle and therefore these cells respond more strongly to for example Ach, compared with bronchial smooth muscle from healthy patients.
proliferative response ( hyperplasia ) ?
The proliferative response occurs in chronic asthmatics. Growth factors elicit mitogenesis and cell proliferation to increase muscle mass. This involves a complex signalling pathway involving growth factors. Bronchoconstrictors can activate this pathway at several points including raf-1 kinase and MAP kinase.
what happens when growth factors bind ?
Binding of growth factors to receptor tyrosine kinase (RTK) causes an intrinsic tyrosine kinase activity in the receptor to phosphorylate the receptor on tyrosine residues. These act as docking sites for proteins that contain so-called SH2 (Src homology) domains that can attach to the phosphorylated tyrosine on the receptor. The first protein to be recruited is called Grb (growth factor receptor binder). This is a cue to activate the guanine nucleotide exchange protein, Sos (son of sevenless) which then activates Ras (via exchange of GDP for GTP on the Ras protein). GTP-bound Ras then activates Raf kinase which phosphorylates and activates many more molecules of MEK, another kinase. MEK phosphorylates and activates many more molecules of the enzyme, MAPK (mitogen activated protein kinase) and in doing so you see a substantial amplification of the original growth factor signal. MAPK is cytoplasmic, but when phosphorylated it can activate gene duplication (DNA synthesis), which is required for the mitosis of cells. It also stimulates protein synthesis so that the daughter cells produced from the parent cell during mitosis has sufficient protein to survive. This pathway underlies the hyperplasia seen in bronchial smooth muscle in asthmatics. Phosphorylated MAPK can also phosphorylate and activate phospholipase A2. This enzyme produces arachidonate, which is needed to make LTD4, a powerful bronchoconstrictor), and in effect converts the smooth muscle cell into a ‘synthetic’ pro-inflammatory cell.
