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