Lecture 3 - Acute inflammation: Main components Flashcards
Acute inflammation
Rapid response to infection/injury (detected in minutes/hours and occurs over days)
Infections
Hypersensitivity reactions
Physical foreign bodies
Chemicals
Tissue necrosis
Macroscopic appearance of acute inflammation
- Suppurative/purulent
- Fibrinous
- Pseudomembranous
- Catarrhal
- Haemorrhagic
- Serous
- Necrotising
Vascular characteristic signs of acute inflammation
Vascular events:
Celsus:
* Redness (rubor)
* Heat (calor)
* Swelling (tumor)
* Pain (dolor)
Virchow :
* Loss of function
Characteristic systemic events
- Fever
- loss of appetite
- Lethargy
- leukocytosis (increase in leukocyte number) & acute phase proteins (see later)
How does the host respond to inflammation?
Deliver leukocytes and plasma proteins to the injury/infection site for removal of necrotic tissue or pathogen:
1) Recognition of tissue damage or pathogen
* Release of chemical mediators
2) Recruitment of leukocytes and plasma proteins to the site
* Increase in blood flow and capillary permeability
3) leukocytes & plasma proteins enter tissues
* Release of chemical mediators
* phagocytosis
* Elimination of pathogen or necrotic tissue
4) repair of tissue
PRRs: what are they, what do they do?
Pattern Recognition Receptors
They mainly recognise two things:
Highly conserved structures in foreign bodies - Pathogen-associated molecular patterns (PAMPs) (e.g., lipopolysaccharide (LPS))
Danger or damage-associated molecular patterns (DAMPs) - released by injured and necrotic cells:
* intracellular proteins, proteins from ECM
* uric acid, K+, reactive oxygen species (ROS), heat-shock proteins (hsp70 and hsp90)
TLR: what are they, where are they found, and what do they do?
Toll-like receptors have 1-13 (1-10 in humans) types
Membrane-spanning proteins located in the plasma membrane & endosome
Recognise pathogens by detecting flagellin, bacterial peptidoglycans, ss/ds RNA, rRNA, profilin, diacyl/triacyl lipopeptides, unmethylated DNA, etc
TLR: what are they, where are they found, and what do they do?
Extracellular region - LRR (leucine-rich repeats) forming a horseshoe-shaped ligand binding domain
Transmembrane domain
Cytsosomal domain - toll interleukin-1
TLR: what are the two main responses
MAP kinases activated:
NF-kb activation resulting in cytokine activation and adhesion molecule expression
Interferon regulatory factors (IRFs) activating antiviral cytokines
What does NF-kb activation result in?
Pro-inflammatory kinases expression
What does interferon regulatory factors (IRFs) activating result in?
INFα and INFβ expressed - increasing viral protection
NOD-like receptors: what are they, what components of them are there, where are they found, how many families are there, and what do they do?
Nucleotide-binding oligomerisation domain receptors
A central NOD, a C-terminal LRR domain, and an N-terminal effector domain (differs between families)
In the cytoplasm
Four families: NLRA, NLRB, NLRC and NLRP - NLRB, NLRC and NLRP function in the innate immune system
Some of the members of the NLRB, NLRC and NLRP families activate inflammasomes, e.g., NLRP3
Detect PAMPs and DAMPs, activates the pro-inflammatory cytokines IL-1β and IL-18, and induce a pyroptosis
NLRP-3 and inflammasome complex
Signal 1 detected by receptor (TLRs) -> NF-kb activated, (I) Pro-IL-β and IL-18 produced
Signal 2 detected -> NLRP3, ASC, and Caspase-1 oligomerise -> Inflammasome formed -> Caspase-1 dimerises and becomes activated -> Caspase-1 activates Pro-IL-β and IL-18 -> IL-β and IL-18 are secreted
NLRP-3: what is its structure, what do mutations result in, and what diseases is it involved in?
Tripartite protein:
- C-terminus LRR
- Central NOD domain (NACHT)
- N-terminus pyrid domain (PYD)
Recurrent episodes of inflammation - cryopyrin-associated periodic syndromes (CAPS)
Alzheimer’s, multiple sclerosis, Parkinson’s disease, atherosclerosis, gout, type 2 diabetes, etc.
ASC: what is it?
Adapter protein apoptosis associated speck-like protein containing a CARD
How powerful is IL-1β?
One of the most potent proinflammatory cytokines - potent endogenous pyrogen
Induces flu-like symptoms such as chills, fever, nausea, vomiting, headache and fatigue when injected into humans at 1–10 nanograms/kg of body weight
Excess production of IL-1 beta is associated with several autoimmune and inflammatory disorders
What two things induce VSM
Nitric oxide (not nitrous oxide (laughing gas)) and histamine induce Vascular Smooth Muscle
What is the triple response to injury?
Red, wheal, flare
Red - vessels vasodilate for a higher blood supply
Wheal - Vessels become more permeable for more fluid release at the injury
Flare - nerve stimulation, impulse in opposing direction for opposing nerve, releasing vasodilation-inducing compounds
What happens to fluid in the blood plasma as it travels through the capillary?
Beginning of capillary (arterial end):
* High hydrostatic pressure gradient (HRG)
* Low oncotic pressure gradient (OPG)
* HRG > OPG so fluid is pushed out of the capillary
End of capillary (venous end):
* Low HRG
* (relatively (~ HRG decreases while ORG remain the same)) High ORG
* ORG > HRG so fluid is drawn back in from interstitial fluid (?)
What happens when a blood vessel has increased vascular permeability?
More fluid is released as well as plasma proteins and neutrophils, resulting in edema in the area
- Caused by vessel trauma (long to repair)
- Endothelial cell injury (short: hours – days)
What chemical mediators cause endothelial cell contraction?
Histamine, bradykinin, NO, complement component C5a, LTB4, PAF, etc
What plasma components are exudated during fluid loss from increased vascular permeability?
Leukocytes:
* Neutrophils (6-24 hrs) - due to the sheer amount in the plasma
* Monocytes (24-48 hrs) > macrophages
Erythrocytes (?) - dependent on size of pores
Proteins (50g/L):
* C-reactive protein (acute phase protein)
* Complement (acute phase protein, see later)
* Immunoglobulins
* Fibrinogen
Leukocyte extravasation
Leukocytes may start to loosely associate with the vessel endothelial cells and may over time form stronger connections and roll along the cells until eventually passing through the cell either paracellularly (between) or transcellularly (through)
What allows the leukocytes to roll along the endothelial cells?
Selectins:
L-selectins - leukocytes
E-selectins - endothelium
P-selectin - endothelium & platelets
Sickle cell disease: what happens to selectins, what does this result in, how can this be treated, and what is the drug that treats it?
Upregulation of P-selectin on endothelial cells and platelets in sickle cell
Promotes binding of erythrocytes to endothelium - vaso-occlusion and sickle cell crisis
Transgenic mice with sickle cell disease and P- and E-selectin deficiencies - protected from vaso-occlusion
Crizanlizumab is a monoclonal Ab that binds to P-selectin and prevents binding to the ligand PSGL-1
Innate immune system: specificity, what does it do, when is it used, how does it do its job, and what does it activate?
non-specific response to pathogens
Includes protective mechanisms, e.g., physical barriers (skin and other epithelial surfaces), mucus layers
first line of defence
components of innate immune system recognise conserved features of pathogens, e.g., viral RNA
initiates adaptive immune response
Adaptive immune system: specificity, what does it do, how does it do its job, and why is it not the first line of defence?
Specific
Remembers previous encounters with specific pathogens and destroys them when they attack again and produces antibodies to destroy the pathogen
It can take time for lymphocytes (T and B cells) to become active and respond so reliant on the innate immune system in the first instance
Cytokines: what are they, what are they produced by, what family are they a part of, what can they do, and what do they often do?
Small proteins secreted by cells during inflammation
Produced by many cell types but macrophages are key manufacturers
Large family of proteins which include chemokines (cytokines with chemotactic properties) and interleukins (cytokines made by one leukocyte which then acts on other leukocytes)
- Can have autocrine, paracrine or endocrine action
- Can be pro-inflammatory, e.g., IL-1β, IL-6 and TNF-α
- Can be anti-inflammatory, e.g., IL-10
Often have ‘cascade’ action: one cytokine stimulates target cells to make additional cytokines: it’s complex
Increased vascular permeability after injury: what happens?
The endothelial cells contract, leaving gaps and allowing plasma proteins and fluid to leave
Predominant cell types in acute inflammation
Neutrophils and monocytes
Predominant cell types in allergic reactions
Eosinophils
Name two characteristic events in acute inflammation
Leukocytosis and increased vascular permeability
Name 5 mediators that are responsible for increasing blood flow to an area of tissue damage or infection
Histamine, Bradykinin, 5-HT serotonin, prostaglandin E2, nitric oxide
Name an example of an acute-phase protein
Complement C38
What is the correct order of events in the adhesion cascade?
Migration, rolling, adhesion, and emigration
Name two chemical mediators produced from arachidonic acid
PGI2, LTB4
What molecules are released from damaged/necrotic cells which activate pattern recognition receptors?
DAMPs
What is the role of opsonin?
Which chemical mediator is directly responsible for causing fever?
Prostaglandin E2
Name three drugs that can be used to slow the progress of the inflammatory disease process
Methotextrate, Chloroquine, Adalimumab - by injection
Name three potential side effects of taking a non-steroidal anti-inflammatory drug (NSAID)
Gastric ulcers, nausea and vomiting, and renal failure
