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136 Cards in this Set
- Front
- Back
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What does inflammation do?
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1. Eliminate foreign invaders
2. Eliminate damaged tissue |
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What is inflammation?
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Protective reponse intended to eliminate the initial cause of cell injury, and necrotic cells/tissue which have resulted from the insult.
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What type of immunity is inflammation?
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Innate
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What is the goal of inflammatory reactions?
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To bring immune cells from blood stream to site of infection.
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What are the important components of inflammation? 3
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1. Cells and molecules (eg. PNMs, lymphocytes, monocytes, platelets, plasma proteins - complement, clotting factors, fibrinogen)
2. Tissue resident cells - macrophages, mast cells, fibroblasts, ECM proteins. 3. Endothelial and smooth muscle of vessel wall. |
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Why do proinflammatory reactions need to be balanced with anti0inflammatory reactions once the stimulus has been removed?
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The proinflammatory reaction can considerably damage the host.
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When does pathology become a dominant feature of an inflammatory reaction?
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1. Reaction is very strong
2. Reaction is prolonged 3. Reaction is inappropriate (eg. allergic response/autoimmune disease) |
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What happens to the damaged tissue as a result of an acute reaction?
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1. They become flooded with exudate closely resembling plasma. It escapes through vessel walls.
2. It is invaded by macrophages. |
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What does exudate do?
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1. dilutes and neutralises irritant chemicals, bacterual toxins etc.
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What are the characteristics of an acute inflammatory reaction?
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- rapid in onset and duration
- exudatation - predominantly PMNs |
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What are the cardinal signs of acute iflammation?
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- Heat
- redness - swelling - pain - loss of function |
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What 3 cardinal signs make up the TRIPLE RESPONSE?
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Heat, redness, swelling
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Why is there heat in an inflammatory response?
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vasodilation and increase in blood flow, accumulation of blood.
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Why is there redness in inflammation?
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increase in metabolic rate.
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Why is there swelling in inflammation?
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increase in blood content, increase in exudate, migration of inflammatrpy cells.
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Why does inflammation cause pain?
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increase in pressure due to accummulation of cells and exudate, partly due to release of chemicals from damaged tissue which stimulates nerve endings.
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What is the VASCULAR RESONSE in inflammation?
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Active hyperaemia:
- swelling of endothelial cells - gradual slowing of blood flow >> thrombosis, rouleaux/sludging, margination. |
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What is rouleaux/sludging?
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Clumping of erythrocytes, mediated by fibrinogen.
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Hyperaemia
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Increased blood flow to tissue.
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Explain how and why exudation occurs during inflammation?
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occurs due to increased vascular dilation and permeability:
- increase in hydrostatic pressure>>inreased passive filtration. - escape of plasma proteins through transient gaps - caused by chemical mediators and tissue damage. |
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What is the effect of mediators overlapping in their function?
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Amplifies the effect
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Inflammatory mediators are often _________ __________ in a _____ or ________ form __________ the body and are released or ________ _________ at sites of _________.
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widely distributed, sequestered, inactive, througout, activated locally, injury.
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Do chemical mediators give feedback?
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Yes positive feedback - they work synergistically.
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How is the inflammatory resonse controlled in terms of mediators?
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They are rapidly inactivated locally after their release.
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What is Histamine?
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- rapidly acting,
- vasoactive amine |
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Where is histamine produced?
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Granules of mast cells and basophils.
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Where is Serotonin produced and what is it similar to?
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Platelets - found in their granules, similar to histamine.
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What are the effects of serotonin and histamine?
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- dilation of small blood vessels
- increased vascular permeability - contraction of smooth muscle |
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Increased vascular permeability occurs in 2 stages - what are they?
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immediate - due to histamine/serotonin
delayed - due to kinins, prostaglandins, leukotrienes |
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What are kinins?
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Biologically active polypeptides
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How are kinins produced? Give an example of a kinin produced this way.
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Action of enzymes called kallikreins on kininogen. Bradykinin is produced this way.
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Where do kallekrein enzymes exist when not in use? When are they activated?
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In plasma as inactive precursors - prekallekreins
During blood clotting. |
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C2-kinin is generated from complement, how?
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Via classical pathway activation
OR action of plasmin (enzyme) |
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When and from what is plasmin generated?
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During blood clotting from plasminogen.
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What is the main function of plasmin?
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To break down fibrin formed during blood clotting.
eg. fibrinolysis - during demolition phase of acute inflammation. |
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What are prostoglandins and leukotrienes?
Are they sythesized or stored? |
fatty acids poduced from the cell membrane
Synthesized by activated cells rather than stored ready for release. |
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PAF
What does it stand for? How is it made? What does it do? |
Platelet activating factor
- synthesized by activated mast cells from membrane phospholipids - causes platelets to degranulate. |
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What is the activation of the complement system inter-related with?
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- kinin and coagulation/plasmin systems
- |
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What do complement fragmenst C3a and C5a cause mast cells to do?
What are they known as? |
degranulate histamine granules
anaphylotoxins |
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What mediators do neutrophils release?
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2 types of cytplasmic granules:
1. azurophilic lysosomal granules - contain proteolytic and other degradative enzymes. 2. specific granules containing proteins. |
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What is the function of azurophilic lysosomal granules?
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- tissue liquifaction
- amplification of inflammation |
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What is the function of the special granules in neutrophiles?
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- anti-bacterial properties
- cause mast cell degranulation |
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What granules do platelets release?
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1. lysosomal granules - contain proteolytic enzymes, cationic proteins
2. dense bodies - contain serotonin |
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What resulst from the digestion of exudate proteins by proteolytic enzymes?
Where are these enzymes derived from? What does the product do? |
Peptides
plasma, tissue cells, neutrophils, sometimes increases vascular permeability. |
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What do bacteria produce that influence inflammtion?
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- kinases
-hyaluronidase - vaso-active toxins - haemolysins - leucocidins - proteases |
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Cytokines
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Protein mediators produced by local cells, induced following an insult.
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In what way to cytokines work?
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Paracrine - activate adjacent cells
Autocrine - stimulate producing cell |
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What do cytokines induce?
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- increased vascular dilation, permeability
- production of proteolytic enzymes. |
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Chemokines
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proteins, act as chemoattractants
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What are the characteristics of chronic inflammation?
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- prolonged,
- leukocytes, macrophages - fibrosis |
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Serous
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Abundant
watery, clear or cloudy liquid Low protein, low cell |
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When is serous observed?
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mild reaction involving serous memebranes, synovia membranes and connective tissue
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Fibrinous
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abundant,
rich in fibrinogen >>> converted to fibrin, deposited as yellow/white elastic |
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When is fibronous exudate observed?
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more severe reactions involving serous membranes, alveoli of lungs and someties connective tissue.
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Catarrhal
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abundant cloudy, thin TO restricted, thick, white, sticky
substantial mucinous content rich in desquamated eputhelial cells and neutrophils |
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What is cararrhal exudate associated with?
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inflammation of mucus membranes of nasopharynx, airways, lower alimentary tract, uterus, mucus glands
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What is suppurative/purulent inflammation associated with?
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associated with bacterial infection by pyogenic organisms - staphlococci, streptococci
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Whats is suppurative inflammation characterised by?
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pus >> abscesses- dying and dead neutrophils and necrotic tissue debris.
Partly liquified by proteases, peptidases, and lipases liberated from dead cells and neutrophils. |
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What determines the colour of pus?
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presence of RBCs and haemaglobin breakdown pigments
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What does the viscosity of pus relate to?
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DNA content
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Cellulitis
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Diffuse pus extending through fascia layers, connective tissue...
Caused by beta-haemolytic streptococci |
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Haemorrhagic inflammation
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occurs during the development of an inflammatory reaction, dominates exudate appearance esp. in organs with rich vascular supply.
Esp if casual agent dmages vessel walls and interferes with coagulation mechanism. |
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Necrotising inflammation:
How does it occur? |
feature of all inflammatory reactions
may be the result of ischemia , or thrombosis, action of potent necrosising toxins produced by certain bacteria |
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What does the exudate do to the lymphatics?
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Holds the walls widely open due to distenion of the tissue spaces. This increases the flow of lymph.
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What may interfere with the lymphatics in a severe reaction?
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Coagulation of fibrin within them.
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Lymphadenitis
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Secondary localisation of inflammation within lymphatics
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Lymphohaematogenous dissemination
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Bacteria get to blood stream via lymph
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Lymphangitits
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Inflammation of lymph vessel
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What are the 2 stages of leukocyte migration?
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1. Margination of neutrophils on altered vascular endothelium - slowing of blood flow, tethering and rolling of WBC
2. active emigration through the gaps between the endothelial cells into tissue spaces. |
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What causes leukocytes and endothelial cells elaborating CAM expression?
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Inflammatory mediators
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CAM
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cell adhesion molecules
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What do tethering and rolling involve the expression of?
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Selectin molecules by the endothelium - tether the WBC
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What do chemoattractant molecules do to the tethered WBC?
Some examples of chemoattractants? |
Actiavte it to express an adhesive form of integrin molecule.
complement, LTB4, chemokines |
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What do the integrins bind to and what dpes it cause?
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CAM - final arrest of cell
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The cells that are tethered in order of appearance:
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Neutrophils (sometimes with eosinophils)
Monocytes >macrophages |
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What are the 2 pathways of neutrophil adhesion:
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1. immediate pathway - (mins) rapid expression of P selectin on endothelial cells by histamine, C5a and PAF. >> neutrophil expression of LFA-1 (integrin) which binds to ICAM-1. (=tighter adhesion)
2. Delayed pathway (2-4hrs) - expression of E selectin by action of IL-1 and TNFalpha - all molecules need synthesized so process is slower. LTB4 and IL-8 cause neutrophils to express LFA-1 which binds to ICAM-1. |
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Monocytes also express receptors for tethering/rolling. What activates monocytes? What is the chemical synthesized by?
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Monocyte chemotactic factor 1 (MCP-1).
Resident macrophages at sight of damage. (LFA-1 still binds to ICAM-1 to mediate arrest). |
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Why is there a delayed appearance of monocytes at sight of infection?
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MCP-1 production is slow.
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Neutrophils and monocytes follow a chemoattractant gradient. What does this mean?
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They move in the direction of the source of the chemoattractant.
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What is phagocytosis promoted by:
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Opsonins
1. Ab 2. complment |
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What facilitates phagocytosis?
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Suitable scoffold - fibrin meshwork, facilitates particle: phagocyte contact.
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Neutrophils
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Short lived end stage cells, cannot resynthesize lysosomal enzymes
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Macrophages
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Long lived, resynthesize enzymes
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How can organisms prevent being killed once phagocytosed?
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Release of toxins, adapt to live intracellularly,
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What are the roles of macrophages in acute inflammation and host defence?
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1. phagocytose pathogens via scavenger receptors, toll-like receptors, Fc, complement receptor.
2. Secrete toxic factors that kill pathogens 3. Secrete cytokines and chemokines that recruit other cells. 4. Secrete colony stimulating factor to promote differentiation and recruitment of monocytes and granulocytes. |
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Leukocytosis
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increase in conc of leukocytes in blood.
usually occurs with specific leukocytes eg. neutrophilia when there is a bacterial or viral infection |
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Temporary neutropaenia
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When circulatiing neutrophils migrate to one site - depletes number of circulating cells.
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Where are relatively mature neutrophils held for when there is an infcetion and they are required?
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haemopoietic tissues
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Neutrophilia
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when many neutrophils are released from storage
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What is neutrophilia induced by?
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IL-1, TNF alpha, IL-8, various CSFs
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What are CSFs synthesized by?
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Macrophages and lymphocytes in response to antigens.
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Shift to the left
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During a prolonged inflammatory process, immature neutrophils are released into the blood - differentiate into mature forms when they reach tissue and local contact with CSF.
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Monocytosis
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Similar mobilization of monoctes
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Eosinphilia
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Inreased number of eosinophils in blood - usually during a parasitic infection.
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Pyrexia
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Fever
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When does fever occur?
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durig more severe reactions
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How is fever induced?
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1. stimulation of macrophages or microbial products >> secretion of endogenous pyrogens >> act on the brain to induce PGE2 >> increase in hypothalamic thermostat.
2. INteraction of microbial products with TLR on brain endothelial cells >> PGE2 is induced... |
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Why is fever beneficial?
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- decreased microbial replication
- increased leukocyte function |
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What happens during an acute phase response?
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1. increased synthesis of several host proteins (eg. SSA)
2. clearing microorganisms 3. blood clotting 4. controlling proteases (synthesized rapidly by the liver) |
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What is the acute phase response mediated by?
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IL-6 released from macrophages, acts on hepatocytes. >> initiates synthsis of acute pahse proteins
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What is anaemia mediated by?
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inflammatory mediators on the liver >> synthesises and secretes HEPCIDIN.
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What does HEPCIDIN do?
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binds a membrane bound iron transporter protein - FERROPORTIN on gut endothelium, macrophages, hepatocytes >>> complex is internalised and destroyed.
Resolution of inflammation begins when hapcidin is turned off. |
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Why is ferraportin important?
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Transports iron form gut, macrophages and liver to plasma>> picked up by TRANSFERRIN >> taken to bone marrow >>> incorporated into haemoglobin
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What happens to RBCs in absence of ferraportin?
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Production is shut off.
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Why does septic shock develop?
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- excessive/poorly regulated inflammation
- maladaptive release of endogenously produced compounds |
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What mechanisms are involved in septic shock?
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- release of cytokines
- activation of neutrophils, monocytes and microvascular endothelial cells - activation of neuroendocrine reflexes. - plasma protein cascade activation - coagulation - fibrinolytic system |
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What does septic shock progress to?
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Multiple organ dysfunction syndrome >>> Multiple organ failure
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Why does DIC occur?
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sepsis disturbs baance between pro and anti coagulant pathways>> widespread thrombosis >> impaired tissue perfusion.
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What does the follow up fo acute inflammation depend on?
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1. the e
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What signals the onset of the demolition phase?
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neutrophil emigaration is replaced by macrophage, plasma cells, lymphocytes which changes exudate.
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Resolution
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complete return to normal architecture of tissue,
removal of cellular debris |
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When does resolution occur?
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When degree of damage is mild
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Resolution programme
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- resolution is active
- switch of inflammatroy mediators - macrophages switch from pro to anti - inflammatory |
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Which cytokines swith to which during resolution?
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Prostaglandins, leukotrienes >>> lipoxins, resolvins, protectins
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What do the mediators do in resolution?
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1. actively antagonise the infiltration of neutrophils
2. promote neutrophil apoptosis# 3. stimulate regeneration of damaged tissue 4. phagocytosis of dead neutrophils by macrophages |
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When a macrophage phagocytoses a apoptosed neutrophil, what happen?
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the macrophages switches from proinflammatory to anti-inflammatory/pre-resolutionary.
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What do macrophages do during resolution?
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Coordinate the healing process:
- remove dead cells, devris, fibrin, lipids, haemosiderin, bacteria, foreign material>> pass out through lymphatics |
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Fibrinolysis
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assists with removal of fibrin,
by PLASMIN |
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Demolition phase
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Clearing up phase
reinstaement of normal blood flow and permeability |
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Lipoxins
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- fatty acid mediators
- precursors derived from archadonic acid, formed via lipooxygenase. |
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Go revise Sequal to acute inflammation.
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Yes siree
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HISTAMINE
What is histamine? What is it involved in? |
Biogenic amine - synthesized within the body
Involved in: Inflammation, anaphylaxis, allergies, gastirc secretion, neurotransmission |
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Which receptors does histamine have its effect by?
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H1, H2, H3, H4
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What does histamine cause?
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Smooth muscle contraction - bronchi, gut, large vessels
Smooth muscle relaxation in small arterioles - fall in BP increases vascular permeability increased secretion of gastric acid |
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Histmine is ________ distributed.
The main storage is in _____ _______. Or in the blood in _________. |
widely
mast cells basophils |
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Where is there a high histamine conc?
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Where there are many mast cells - skin, bronchial and intestinal mucosa.
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Which enzyme causes histadine >>>> histamine
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L-histidine decarboxylase
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What else produces histamine?
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CNS neurons, gastric mucosa parietal cells, lymphocytes
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What is a site of slow histamine production?
Fast production? |
Mast cells - produced and stored, turnover is slow.
Gastric mucosa - to control gastric acid |
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What are the effects of histamine in
Carnivores? Rabbits? Guinea pigs? |
Hypotension (decrease BP)
Bronchocondriction and right heart dilation (increase in BP) Bronchoconstriction and asphyxiation |
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Histamine release in allergy: what happens?
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Antigen reacts with IgE on mast cells surface
INcrease in intracellular Ca Release of complexed histmine - active Release of hitamine from granules |
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When can the release of histamine be modified?
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If chronic inflammation exists
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Name drugs and chemicals that cause histamine release:
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Neuromuscular bloking agents
opiod endogenous mediators - bradykinin, kallidin, substance P |
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Name the 3 things which cause histamine release?
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Allergy
Drugs/chemicals Physical injury |
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Which receptors did original antihistamine drugs tartget?
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H1
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What does H2 do?
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Control gastric acid secretion
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