Physiology of Inflammation Flashcards
5 cardinal signs of inflammation
- calor (heat)
- rubor (redness)
- tumor (swelling)
- dolor (pain)
- functio laesa (loss of function)
3 phases of inflammation
1) Initiation
- stimulus occurrence and its recognition
- local production of inflammation mediators
2) Patent inflammation processes
- local dilation of capillaries increase blood flow
- micro vascular structural changes and escape plasma proteins from the blood stream
3) Resolution
- removal of stimulus
- inhibitory feedbacks and counter- balanced cellular and humoral responses
- repair, wound healing, if adaptive- memory development
Causes of inflammation
- infections or microbial specific exotoxins, endotoxins and pathological mechanisms
- tissue injury/ death
- hypersensitivity
Examples of inflammatory diseases
- Gout
- IBS
- rheumatoid arthritis
- autoimmune diseases
Morphological patterns of inflammation
- Serous
- fibrinous
- haemorrhagic
- suppurative
- necrotising
- ulcers
2 classifications of inflammation
- Acute
- Chronic
Features of acute inflammation
- fast onset
- prominent signs
- mild outcomes
- self limited
Features of chronic inflammation
- slow onset
- less prominent signs
- severe outcomes
- progressive disease
Examples of acute phase proteins
- ↑ CRP
- Fibrinogen
- Haptoglobin
What happens in stimulus occurrence?
Infection
- virus
- bacteria
- fungi
- eukaryotic parasites
What happens in stimulus recognition?
Humoral factors
- complement system
- antibodies
- other proteins
Innate cell recognition
- PRRs (Toll-like receptors)
- complement and antibody responses
Adaptive immuno-recognition
- specific responses
What does PAMPS stand for?
Pathogen associated molecular patterns
What does DAMPs stand for?
Damage associated molecular patterns
What does SAMPS stand for?
Self/suppression associated molecular patterns
Feature of the initial local mediator release
Autocrine and paracrine cellular responses:
- mediated by diverse cell types and vast ranger of different receptors
- release of other mediators by surrounding cells, local and systemic responses
Mediators of inflammation and examples
- Amines (histamine)
- Lipids (prostaglandins, Leukotrienes
platelet-activating factor) - Peptides (bradykinin)
- Proteins (cytokines)
- Chemokines
- Enzymes
How does vasodilation occur?
Mainly due to histamine and NO
- released by mast cells and macrophages
- also promoted by PAF, bradykinin PGE1 and 2
What causes swelling?
- micro vascular leakage occurs in post capillary venules
- mainly due to histamine
endothelial cells retraction and rearrangement of tights-junctions forming gaps between them and allows fluid exudation - loss of protein leads to oedema
Where is histamine released from?
What do histamines do? (2)
- Mast Cells
- dilate blood vessels
- ↑ micro vascular permeability
What is the function of Histamine H1 receptors?
G protein couple receptor
- ↑ Ca2+
- smooth muscle contraction
- ↑ capillary permeability
- vasodilation
- sensory nerve endings pain and itching
IMPORTANT- for asthma and allergies
Lipids as mediators of inflammation (4)
1) stored in phospholipid molecule
2) enzyme phospholipase A2 breaks down phospholipids
3) IFN-y, IFN-a, b-FGF receptor - phosphorylation and CA2+ influx
4) Phospholipid broken down into Arachidonic acid and Lyso-glyceryl-phosphorylcholine (Platelet activating factor)
How is platelet activating factor produced?
Produced mainly by platelets, mast cells, neutrophils, macrophages, endothelial cells:
1. Phospholipids
2. Lyso-glyceryl-phosphorycholine
3. Platelet activating factor
4. PAF-receptors
What does platelet activating factor do? (8)
- Strong vasodilation
- ↑ vascular permeability
- bronchoconstriction
- platelet aggregation and degranulation
- leukocyte chemotaxis, extravasation
- promote neutrophil oxidative burst
- ↑ production of eicosanoids by inducing Cox2 transcription
- ↑ transcription of IL-6, MMPs and iNOS
Eicosanoids precursors
Arachidonic acid (20 carbon lipid)
EPA = Eicosapentaenoic acid (omega-3 fatty acid)
DHA = Docosahexaenoic acid ( 22 carbon omega 3 fatty acid)
What can eicosapentaenoic acid (EPA) form?
What can docosahexaenoic acid (DHA) form?
- Resolvins
- Resolvins
- Protectins
- Maresins
What do eicosanoids effects depend on? (3)
- half life
- type of receptors they interact with
- each cell type has a different set of eicosanoids synthetic enzymes, receptors and responses - so competent to produce and release a variety of molecules
NSAIDS as cyclooxygenase inhibitors
- Inhibit Cox1 and Cox2
- so block synthesis of PGs and TXs
arachidonic acid → (Cox +O2) → PGH2 → PGE2 etc.
Function of PGE2 (4)
Gastric protection
↑ mucus secretion
↑ bicarbonate
↑ mucosal blood flow
(Cox1 inhibition causes peptic ulcers and GI bleeding)
Adverse effects due to Cox1 inhibition (3)
What should you prescribe?
↑ gastric acid secretion
↓ gastric/ duodenal mucus/ HCO3- secretion
↑ risk of GI ulceration
- prescribe PPI for gastro- protection or using co-formulation (e.g.naproxen + esomeprazole)
Eicosanoids Leukotriene example
LTB4
- made by neutrophils & erythrocytes
- G-coupled receptors
- pro-inflammatory
- neutrophil chemotaxis
- activation of transmigration
Eicosanoids lipoxins example
LXA4
- produced by neutrophils
- G couple receptor
- modulation of LKs and cytokine action
- control resolution of inflammation by stopping neutrophil chemotaxis, adhesion and transmigration
- inhibit NK functions
Glucocorticoids mechanism of action
1) Bind to cytoplasmic GR receptors (normally inactive and associated with HSPs)
2) Upon binding, HSP dissociate and activated receptors dimerise
3) Dimer of activated receptors translocate to nucleus
4) In nucleus, dimers bind to DNA-motifs called glucocorticoid response elements (GRE)
5) Gene transcription modified
Effects of glucocorticoids
- inhibit transcription of pro-inflammation genes
- Cox2, IL-2, TNF-a, IL-1, IL-4, adhesion molecules
- induce expression of anti-inflammatory genes
- lipocortins (annexin 1) IL-10, IL-1ra
annexin 1 interferes with phospholipase A2: inhibit leukocyte activities and activating lipoxin A4 receptor
Adenosine functions
MACROPHAGES (A2A, A2B, A3):
- ↓ TNFa, IL-6, IL-22
- ↑ IL-10
DENDRITIC CELLS:
- A1/A3: regulation of chemotaxis & maturation
- A2A: ↓ pro-inflammatory cytokine release
- A2B: ↑ Th17 mediated response
- A2B:↑ TNF-a, IFN-y, IL-6/8, TGF-b, VEGF, Cox2
MAST CELLS:
- A2B: regulation of degranulation
- A1/A3: ↑ chemotaxis and phagocytosis
NEUTROPHILS (A2A):
- ↓ neutrophil adhesion
- ↓ phagocytosis
- ↓ IL-8 and ROS
LYMPHOCYTES (A2A):
- ↓ IL-4 / IFN-y
- ↑ NF-kB in T regs
- maintenance T/B cells ratio in germinal centres
Major mediators of inflammation:
Enzymes (complement system) (5)
- Ig-Ag, microbial surface, polysaccharide
C3a = inc vascular permeability
C5a = inc vascular permeability, chemotaxis
C3b = opsonisation
C3b-C9 (MAC) = cell lysis
Major mediators of inflammation:
Enzymes (coagulation fibrinolytic cascades) (3)
Adhesion of thrombin → fibroblast proliferation
Fibrinopeptides factor Xa → vascular permeability and leukocyte exudation
Plasmin → C3a
Major mediators of inflammation:
Enzymes (kinin system)
Hageman factor → ( tissue injury) → bradykinin → pain, vasodilation, increased permeability
(- Hageman factor converts Prekallikrein to kallikrein
- Kallikrein converts Kininogens to Bradykinin)
Features of phosphorylesterases (PDEs)
PDEs:
- enzyme superfamily
- control cAMP and cGMP catabolism
They have different:
- subcellular distribution
- enzymatic activity
- kinetic properties
- substrate specifity
- cell type-specific
- cell responses
Mediators of inflammation:
Features of Cytokines (10) and Chemokines (1)
- promote differentiation, proliferation and activation of leukocyte
- promote leukocyte adherence to endothelium (IL-1, TNFa)
- promote leukocyte production in bone marrow (IL-3)
- promote B-lymphocyte class switching (IL-4, INFa)
- activate local tissue destruction 9 (IL-1b, IL-17)
- regulate chemokine production (IL-17)
- induce of acute phase protein production at liver (IL-6)
- induces haemoatopoietic GF (IL-17)
- induce vascular changes (IL-1,IL-17, IL-6)
- kinase-linked receptors
- chemokines attract leukocytes (CXCL)
