cpat module 1

inflammation, neuroinflammation, immunology

acute inflammation major cell type

neutrophils

chronic inflammation major cell type

monocytes / macrophages

inflammation can be the

cause of disease rather than the pathogen directly

acute injury blood test

• high leukocytes

• increased proportion of neutrophils (neutrophilia)

healing depends on

the degree of injury

• no bacterial entry = fastest

• bacteria = minutes to days

• tissue damage = weeks

host defences against micro organisms

• barriers → epithelial, secretions, preformed non specific effectors

• activation of immune systems - macrophages, phagocytosis, complement

• antigen movement

• switch to adaptive immunity

switch from. preformed non specific innate effectors to macrophage and phagocytosis activation

takes more than 6 hours

• after macrophage activation, antigen drains to lymph nodes, further exposure to NK cells and macrophages

• humoral and cellular immunity activation

roles of inflammation

1. defence against micro organisms

2. elimination of damaged cells, inanimate foreign particles

3. initiation of healing processes (early problems lead to long healing impairment)

inflammation

the reaction of vascularised living tissues to local injury or infection, characterised by the movement of fluid and leukocytes from the blood into the affected tissue

acute inflam

• rapid onset

• relatively short lived

• sterotypic response to injury or infection

• movement of fluid and neutrophils out of the blood and into affected tissue

• can evolve to chronic, but its rare

chronic inflam

prolonged inflammation due to injury or infection

appendicitis histology

• acute inflammation

• spaces filled with oedema fluid

• neutrophils marginate in blood vessels, they also infiltrate the tissue

positives of inflammation

• promotes host survival

• initiates adaptive and innate immunity

• host defence against micro-organisms

• initiates healing

negatives of inflammation

• deleterious effects on host survival

• acute - perforation of wall can kill patients, meningitis (intra cranial pressure)

• chronic - tissue destruction in TB, incapacitation in arthritis, initiates cancer

major cell types in inflammation

• neutrophils - kill pathogen

• endothelial - regulates movement of proteins from blood into tissues

• macrophages - degrade fibrin and debris, kill pathogen, secrete cytokines

• fibroblasts - secrete collagen for healing

acute inflammation can occur in response to

1. sterile injury

2. injury with infection

3. infection without injury

in all cases, processes are the same

cardinal signs of inflammation

1. redness

2. heat

3. swelling

4. pain

as described by aulus celsus

these are visible/tangible signs of the physiological response to injury

heat + redness

occurs due to increased blood flow (hyperaemia)

redness aka erythemia

swelling

due to fluid movement from blood into tissue (exudation), movement of cells

pain

mediated by pain receptors

• increasing sensitivity of pain receptors = hyperalfesia 

• all inflam mediators, can reset the sensitivity level of the pain receptors

Oedema

accumulation of fluid extra vascularly in tissues 

Exudate

oedema fluid with high protein content, resulting from increased endothelial permeability to plasma proteins in inflammation

pus

 inflammatory exudate containing viable and dead neutrophils, cell debris, viable and dead micro-organisms, protein, lipid, DNA

hyperaemia

• Hyperaemia is the passage of larger-than- normal volumes of blood through a tissue (vasodilation)

• Not specific to inflammation – e.g. usually occurs during exercise

• Hyperaemia is essential in inflammation – for the formation of the exudate

• increased RBCs

Hyperaemia in acute inflammation

• Heat” and “redness” are consequences of hyperaemia.

• Hyperaemia is an increase in the amount of blood flowing through an area of tissue.

Hyperaemia results from:

1. vasodilatation of the pre-capillary arterioles

2. opening up of dormant capillaries to the passage of blood

Vasodilation causes hyperaemia in acute inflammation

• Locally produced vasoactive mediators of inflammation act on arteriolar smooth muscle cells.

• Relaxation of the smooth muscle cells allows the arteriole to dilate.

• More blood is able to enter the microvascular bed.

• Capillaries that were “dormant” (filled with plasma) start to carry blood

exudation

• due to dramatic increase in permeability of endothelium.

• After initial hyperaemia, fluid (containing plasma proteins) moves from the blood into the affected tissue. 

• Increased vascular permeability to proteins must happen for exudation to occur.

• The fluid movement leads to slowing of blood flow in the affected area. The vessels appear “congested.”

• Swelling results from the increased fluid content of the tissue.(macroscopic)

• Accompanying the fluid movement is emigration of neutrophils into the affected tissue

how does exudation occur?

Mild or moderate acute inflammation: Through inter-endothelial gaps in post-capillary venules only (contraction of endothelial cells).

Two patterns:

• immediate but transient

• delayed and prolonged

more severe = damage to endothelial of all microvessels - immediate prolonged response

forces at the vessel walls

hydrostatic P → pushes out of the vessel

osmotic P → pushes into the vessel

normally → balance between these forces allows control of fluid movement

movement of fluid in acute inflammation

artiole → vasodilation allows more blood flow, hydrostatic pressure increased which drives fluid out of the vessel (transudation). Colloid osmotic pressure decreases as EX protein conc increases. — substaintial net loss of fluid from microcirculation

post capillary venule - vasoactive mediators act on endothelial cells in the venules, causing gaps to open between them. Plasma proteins (eg, antibodies) move out of vessel into EX fluid.

Role of Exudation

fluid → dilutes toxins, increases flow into lymphatics

plasma proteins → antibody, complement components, fibrin, all moved into tissue for repair

neutrophils moved to destory micro-organisms

types of inflammatory mediators

1. vasoactive

2. chemotactic

vasoactive mediators

• increase blood flow and vascular permeability to protiens

• aka cause exudation

chemotactic mediators

recruit and stimulate inflammatory cells

• results in either acute or chronic inflammation

ex, vasoactive mediators

1. Amines -  histamine

2. Lipid-derived mediators • prostanoids • leukotrienes

3. Plasma-derived mediators • complement fragments 3a and 5a (“C3a and C5a”) • kinins

histamine source

mast cell degranulation

platelets

role of histamine in inflammatory response

• vasodilation of arterioles

• increase vascular permeability in post capillary venules

NB: there are a number of clinical anti-histaminic drugs, but these have little anti-inflammatory activity.

formation of lipid derived mediators of inflammation

membrane phospholipid phosphilpase A2 is activated by inflammatory stimuli

→ arachidonic acid -> cyclo-oxygenases or lipoxygenases

cyclo-oxgenases → prostanoids

lipooxygenases → leukotrienes

corticosterooids block

phospholipase A2, so development of prostanoids and leukotrienes

NSAIDs block

cyclo-oxygenases So prostanoids

zileuton blocks

lipooxygenases so leukotrienes

summary of vasoactive mediators

vasodiltion → histamine, kinins, prostaglandin E2 and I2

increased vasc perm → histamine, Kinins, C3a, C5a, leukotrienes B4 and C4

sensitisation of pain receptors

done by prostaglandins