Pathology of inflammatory responses Flashcards
Acute inflammation vs chronic inflammation. Which leukocytes are involved
Acute: short lived and neutrophil rich
Chronic: long-lived and lymphocyte, plasma cells and macrophage rich
Characteristics of acute inflammation
PRISH
What is the exudate which is generated in acute inflammation?
Fluid rich in protein and/or cells
- Contains fibrinogen which is converted to fibrin that forms a mesh = scaffold for healing and repair
The acute inflammatory response process
- Pathogen binds complement C3
- Activation of complement cascade
- Release of histamine and chemoattractants
- Altered permeability of local vasculature allows fluid exudation (oedema)
- Altered adhesiveness of endothelium allows cellular migration (extravasation by diapedesis)
- Phagocyte recognition of C3b - oponised pathogen!
Cellular and plasma mediators of acute inflammation
Cellular:
- Vasoactive amines
- Cytokines and growth factors
- Arachidonic acid derivatives
- Platelet activating factor
- Lysosomal enzymes
- Oxygen radicals
- Nitric oxide
Plasma:
- Kinin system
- Coagulation and fibrinolytic system
- Complement system
3 major molecular pathways for regulating acute inflammation
- Complement cascade
- PAF
- Arachidonic acid metabolic pathway
Explain the actions of the platelet activating factor (PAF)
Contributes to: inflammation, endotoxic shock, allergic reactions (involved in vasoconstriction and bronchoconstriction)
Has an impact on platelet aggregation and leukocyte adhesion
- At low conc, PAF causes vasodilatation rather than vasoconstriction
- Direct effect on cells contributing to the INNATE immune response, particularly neutrophils where it enhances their microbicidal activities through oxidative burst
- Many of the downstream effects of PAF come from it activating the arachidonic acid pathway!
What can PAF be derived from?
It is a phospholipid
- Derived from:
1. Platelet cells
2. Basophils
3. Mast cells
4. Neutrophils
5. Macrophages
What are acute phase reactions? Examples
Not directly related to cells or local responses at site of injury, but largely as a result of acute phase proteins from the liver in response to signals originating from the local inflammatory site
Example: Increased bone marrow leukocyte production
Consequences of acute phase reactions?
- Fever: Due to increase pyrogen molecule production (endogenous pyrogens IL-1 and IL-6 reset hypothalamus set temperature)
- Rigors
- Tachycardia
- Drop in BP
- Vomiting
- Loss of appetite
- Skeletal weakness
- Aching
- Altered liver metabolism - acute phase proteins
- Hypothalamus-pituitary-adrenal axis: altered metabolic changes leading to general malaise
What are the 4 stages of inflammatory response due to lobar pneumonia (strep. pneumoniae)
- Congestion
- Starts within 1st 24hrs
- Lungs are filled with protein rich fluid (fibrin) which goes into the alveolus
- This point is not RBC or neutrophil-rich - Red hepatization / consolidation
- 2-3 days after initial insult
- Consistency becomes like a liver: dry, granular, airless
- Neutrophils and RBCs enter alveolus
- We get fibrin deposition replacing oedematous fluid from the congestion phase, leading to solidification - Grey hepatization
- Grey lung looks like a cooked liver, due to fibrin exudate
- Disintegration of red cell and deposition of haemosiderin as a result
- Macrophage recruitment to eat dead neutrophils and begin digestion of fibrin mesh - Resolution
- Restoration of normal tissue when architecture is intact (when resolution not possible, we have repair)
- Takes place around 8 days after infection
- Begins centrally in lung lobe and spreads peripherally, we get liquefaction of all fibrous deposits from previous stages, allowing aeration back into alveoli
- Macrophages dominate this stage - Organisation
- When resolution not possible, we switch to repair.
- Usually associated with scar formation
What is an abscess?
Accumulation of neutrophils walled off by fibrin and surrounded by chronic inflammatory cells (macrophages and fibroblasts)
- A chronic condition of persistent acute inflammation
- This is an example of suppurative inflammation
- May require surgical excision
What mediators are involved in resolution of inflammation?
- THIS IS AN ACTIVE PROCESS
- Lipoxins
- Resolvins
- Protectins
- These allow early resolution of inflammatory response rather than entering chronic inflammatory phase following the acute inflammatory phase
- Clinically important as if we there are active processes to trigger resolution, we can have drugs candidates for modifying this process!
What are the 4 types of chronic inflammation?
- Non-specific
- Supervenes after acute infection, as in helicobacter-associated gastritis, characterised by lymphocytes (B and T) and plasma cells
- Commonly follows persistent viral infections such as Hep B - Chronic suppurative
- Relates to abscess formation
- Osteomyelitis
- Continued stimulus to neutrophil production and recruitment
- EOSINOPHIL RICH, often indicates underlying parasitic infection - Granulomatous
- Usually response to agents which are difficult to destroy using lysosomal enzymes or lymphocyte-mediated immune responses.
- Multinucleated / epithelioid cells form by fusion (TB)
- Sometimes the causative agent is unknown - Crohn’s or sarcoidosis - Auto-immune
- Involves largely lymphocytes (T, B, plasma cells)
- If this persists for a very long time, its possible to notice tertiary lymphoid structures at the site of inflammation = poor prognostic indicator
- e.g rheumatoid arthritis
What is a granuloma? Features
- Dominant cell type is the macrophage
- Site of chronic inflammation
Features:
1. Epithelioid cells - macrophages which start to resemble but have not transformed into cuboidal epithelial cells = used for indication
- Multi-nucleated giant cells
- Acquisition of multiple nuclei is a feature
- Sometimes due to failure of cell division with nuclear division still occurring
- Mainly due to fusion of multiple macrophages within the granuloma giving rise to a large cytoplasmic mass with multiple nuclei contained within
- When they have a horse-shoe arrangement, it is called a langhan giant cell
