ML Watson Lec 1 & 2 Flashcards
What is the role of sensory neurones in inflammation?
- Mediate nociception (perception of noxious things e.g pain)
- Release neuropeptides (substance P and CGRP)
What do neuropeptides generally do?
- Contribute to redness and swelling by acting on blood vessels and pain receptors
What does CGRP stand for?
What is its role?
- Calcitonin-gene related peptide
- It is a potent vasodilator that induces erythema (reddening)
What does substance P act on?
What effect does this have?
- NK1 receptor on endothelial cells
- Stim further histamine release from mast cells
- Induces oedema formation (wheal) at injection site, local reddening and flare due to sensory nerve mediated axon reflex
- Induce cytokine release
Talk through the 4 steps of neuropeptide induced inflammation in the skin…
1) Injury is followed by mast cell activation and histamine and PG release
2) PG causes vasodilation and Histamine activates sensory neurones via H1 receptors to stimulate orthodromic stimulation to spinal cord and antidromic stimulation to surrounding skin which leads to neuropeptide release (Sub P and CGRP)
3) Sub P acts via NK1 receptors on endothelial cells of postcapillery venues or by causing increased histamine from mast cells to mediate plasma extravasation at trauma site
4) Substance P increases blood flow but CGRP acts via CGRP receptors and is a potent, long lasting microvascular dilator - this mediates the FLARE at site of injury
How does SP affect microvascular permeability?
- SP affects microvascular permeability via two main mechanisms:
- via endothelial NK1 receptors to increase plasma leakage
- via mast cells, which SP activates to release oedema inducing mast cell amines (histamine)
1) In RA what mediates bone erosion?
2) SPECIFICALLY…
3) What secretes these?
- Proteinases
- MMPs (Matrix metallo proteinases)
- Tissue cells such as synovial fibroblasts and chondrocytes
1) What activates tissue cells that secrete these bone eroding proteinases?
2) What drives this?
1) Infiltrating leukocytes
2) Driven by inflammatory mediators and cytokines, derived from macrophages (TNF-a, IL-1b)
What helps to maintain cytokine production?
- T and B lymphocytes
What is angiogenesis?
- Physiological process through which new blood vessels form from pre-existing vessels
What cell types infiltrate a rheumatoid joint?
- Lymphocytes
- Macrophages
- Interdigitating cell
- Plasma cell
Why does inflammation occur in a rheumatoid joint?
- More blood vessels are formed (angiogenesis)
- Vessels are leaking due to SP
- Cells infiltrate
Where do macrophages arise from?
What are they a major source of?
- Blood monocytes
- Cytokines e.g IL-1, TNF, chemokines TNF (lead to inflam)
What are lymphocytes defined by?
- List some lymphocytes
- Surface antigens, the cytokines they make and function
- T cells (CD3+):
- T helper cells (CD4+)
e. g Th1, Th2 - Cytotoxic T cells (CD8+)
- Natural killer (NK, NKT)
- Th17
- Regulatory T cells (T reg)
- B cells
- Mature to become antibody secreting ‘plasma cells’
What do T cells do?
What can an imbalance or inappropriate activation of T cell subsets lead to?
- Control specific immune system
- Secrete different cytokines associated with diff immune responses
- Th cells activate B cells leading to production of antibodies
- DISEASE
Where does ATP that targets vasculature and leukocytes come from?
- Cell stores (from nerves and inflammatory cells)
What do cytokines target?
- Leukocytes (WBC’s) and tissue cells
Do chemical mediators of inflammation have a LOW or HIGH specificity?
- LOW (not antibodies)
How can inflammation be beneficial? (2)
Increased supply of cells and chemical mediators to site of inflammation:
1) Redness: inc blood flow
2) Swelling: inc vascular perm
Allows removal of damaged tissue, infectious agents
Tells body to rest
1) Pain
2) Loss of function
Acute and chronic inflammation mechanisms overlap
- List the aspects of acute and chronic inflammation..
Acute:
Redness, swelling, chemical mediators, neutrophil recruitment
Chronic: Cytokines, macrophage and lymphocyte recruitment
List the different mediators that respond to local injury:
1) Pre formed mediators - Histamine
2) Production of mediators from membrane lipids - eicosanoids (PGE2, PGI2) leukotrienes (LTB4), PAF
3) Release of peptides from stimulated neurones - SP, CGRP
4) Mediator production following proteinase activation - bradykinin, complement fragments (C3a, C5a)
5) Hours later production following protein synthesis - iNOS, COX-2, cytokines
What effects does Histamine have on local blood vessels?
- Vasodilation
- Increases vascular perm
- (but bronchoconstriction)
Which eicosanoids are vasodilators?
What are the others responsible for?
PGE2, PGI2, LTB4, LTC4
- PGE2, PGI2 = vasodilators
- LTB4, LTC4 = increase vascular permeability
Name some agents that increase plasma leakage via an action directly on the endothelium…
- Histamine, bradykinin
