Acute Inflammation Flashcards
(18 cards)
Appreciate the role of inflammation on disease
- A protective response intended to eliminate the cause and consequence (dead cells) of cell injury by:
o Dilute
o Destroy
o Neutralise
o Initiate resolution (repair) - Process that destroys and eliminates microbes and necrotic tissue but can also injure normal tissue
- Without inflammation, infections would go unchecked, and wounds would not heal
Know the difference between acute and chronic inflammation
Acute vs Chronic inflammation:
- Acute
o Rapid onset, short duration
o Fluid, plasma protein and cellular exudate
o Neutrophilic leukocyte accumulation
- Chronic
o Insidious onset
o Long duration
o Lymphocytes and macrophages
o Scarring
Know the features and mediators of vascular change (step 2 inflammation - recruitment) and recognise the determinants of vascular permeability
Rapid response designed to deliver leukocytes and plasma proteins to the site of injury by:
- vasodilation
- increased vascular permeability
To dilute, neutralise and destroy the cause and consequence of injury.
Vascular change + permeability:
> Vascular injury
> Transient vasoconstriction
> Arteriolar vasodilation (vasoactive mediators) - leads to increased blood flow (redness/erythma)
- macrophages and dendritic cells after recognition will release pro-inflammatory cytokines
- Pro-inflammatory cytokines cause Vasodilation by signalling mast cells to release histamines, leukotrienes, NO, bradykinins and prostaglandins
- Later, - IL-I and TNF cause endothelial cells to express adhesion molecules
> vasodilation leads to Vascular permeability due to the retraction of the endothelial cells, creating gaps between cells through which plasma proteins can escape
1. vascular permeability disturbs laminar flow creating stasis
- stasis causes RBCs to accumulate in centre and monocytes and neutrophils towards vessel wall
2. Exudate escapes (fluid rich in proteins + cells) and is a form of plasma
- Leakage of plasma causes less fluid in intravascular space as it accumulates causing swelling (edema) in extravascular space
- Resulting in thick blood and concentrated RBC’s in the vessel
Vascular change (lymphatics)
- interstitial fluid is normally drained by lymphatics
> During inflammation:
- increased lymph flow
- drain edema
- drain cells, cellular debris, microbes
Know the features and mediators of leukocyte recruitment, including the role of adhesion molecules (step 2 - recruitment (cellular changes))
- Margination
o Slowed blood flow-stasis
o Leukocytes are pushed to the “margins” of blood vessels
o Tumble along the endothelial surface-“rolling” - Rolling
o Weak transient adhesion
o Reduces rolling velocity
o Mediated by selectins on endothelial cells (upregulated by IL-1 and TNF during injury)
o selectins bind to Sialylated oligosaccharides expressed on glycoproteins - Adhesion
> Mediated by integrin receptors
- Expressed on the leukocyte plasma membrane
- Low affinity until activated by chemokines
- Leukocyte activation clustering of integrins high affinity
> Inflammatory cytokines stimulate endothelial cell expression of integrin ligands (I-CAM, V-CAM)
- causes firm adhesion - Transmigration (also called diapedesis)
o movement of leukocytes between cells at the intracellular junctions (between endothelial cells)
o In response to the chemical gradient produced at the site of inflammation that guides leukocyte to exact site of injury
o mainly occurs in Post capillary venule (thin-walled, ideal for passage) - Chemotaxis
- Leukocytes arrived in extravascular space
- Migrate towards infection/injury by Chemotaxis-a chemical gradient produced by exogenous (infection/microbial products) and endogenous (host factors like cytokines, chemokines) sources
> How Chemokines and Chemotaxis Work Together:
- The injured tissue or infected cells release chemokines into the surrounding area.
- Leukocytes in the area detect the chemokines because they have chemokine receptors on their surface
- The leukocytes “move” (through chemotaxis) toward the highest concentration of chemokines, which is usually the site of infection or injury.
Understand how vascular events cause the cardinal signs of inflammation
Cardinal/classic signs of inflammation
1. Heat
- due to Vasodilation, increased blood flow to the injured region
- Redness (erythema)
- Vasodilation, congestion/hyperemia/engorgement
- due to increased blood flow - Swelling (edema)
- Vasodilation & vascular permeability leading to extravasation of fluid (transudate/exudate/edema) or leakage of plasma fluids - Pain
- Compression of tissues
- due to Direct effect of inflammatory mediators - Loss of function
- Direct effect of injury
- due to both Pain and swelling (edema)
Describe how recognition (step 1 inflammation) of the causes and consequences of injury leads to the activation of leukocytes
The body first recognizes there’s a problem, like an infection or injury.
The goal is to get rid of what’s causing the damage (like bacteria or foreign objects) and clean up the mess (dead cells or tissue).
- Phagocytes and dendritic cells (cells that reside in the connective tissue of organs) and many other cells (epithelial cells) express receptors that sense the presence of microbial pathogens and substances released from dead cells
> Pattern recognition receptors (PRR):
- Toll-like receptors recognise patterns that are unique to bacteria, viruses and other pathogens
- Inflammasome recognises products of dead cells and some microbial products
- Pattern recognition receptors detect the cause or consequence of injury and cellular changes that lead to the recruitment of leukocytes to the site of injury
- PAMPs and DAMPs are molecules found on or released by different things.
- Both are detected by the immune system using pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) or inflammasomes to start inflammation.
- PAMPS - detected by toll-like receptors
- Lipopolysaccharides
- Lipotechoic acid
- Unique surface glycans
- Viral RNA - DAMPS - detected by inflammasomes
- Uric acid (DNA breakdown)
- ATP (mitochondria)
- Decrease in K+ (ion channel failure)
Explain the process of phagocytosis and describe the phagosome, lysosome and phagolysosome
Phagocytosis
- Binding of opsonised particles to phagocyte triggers engulfment and membrane remodelling and cytoskeletal changes
- Actin filaments of phagocyte assemble beneath the plasma membrane to extend it around the microbe.
- phagocyte membrane zips up around microbe (now its called a phagosome)
- Phagosome fuses with the membrane of lysosome forming the phagolysosome
- Exposes the ingested particle to a destructive process (free radicals/enzymes)
Explain how free radicals and enzymes contribute to killing and degradation of the cause and consequence of injury
- Killing (gets rid of cause)
- inactivates/kills the microbe (not viable/cant replicate)
> ROS
- Triggered by a respiratory burst (sudden increase in oxygen consumption).
- Driven by NADPH oxidase (aka phagocyte oxidase):
- Inactive in cytosol; only active once moved to the phagolysosome membrane.
- Generates superoxide (O₂⁻), which converts to:
- Hydrogen peroxide (H₂O₂)
- Hydroxyl radicals (*OH)
- These ROS directly damage microbial lipids, proteins, and DNA.
> RNS
Nitric Oxide (NO)
Endothelial cells produce eNOS
Macrophages and neutrophils produce iNOS
Short lived, free radical gas
Reacts with superoxide to form perocynitrite
Cytotoxic agent in macrophages
And other roles in inflammation
* Vasodilation
> Enzymes
1. Bacterial permeability increasing enzyme
- Phosoholipase-mediated membrane degradation
2. Lysozyme
- Oligosaccharide coat degradation
3. Major basic protein
- Cytotoxic to parasites
4. Defensins
Create holes in microbe membranes
- Degradation (gets rid of consequence of injury - dead cells)
- Break the dead microbe
> Lysosomal Acid Proteases
- Function inside the lysosome, at low pH.
Responsible for degrading:
- Microbial proteins
- Damaged organelles
- Ingested cell debris
> Neutral proteases
- Active in extracellular matrix (ECM) and neutral pH environments.
- Important for clearing extracellular debris, breaking down structural components, and facilitating tissue remodeling.
Key examples:
1. Elastase
2. Collagenase
3. Cathepsins (some types function extracellularly)
Explain why the inflammatory response can also cause tissue injury
What If Resolution Fails?
Chronic inflammation can follow:
- If the offending agent persists
- Or if damage is too severe
Fibrosis may result:
- Seen when there’s substantial tissue destruction
-involves collagen deposition and formation of scar tissue
- Leads to loss of function in severe cases
Understand how acute inflammation is resolved (Step 4 - resolution)
Resolution occurs if:
- Injury short-lived
- Minimal damage
- Regeneration and repair of damaged tissue
- Regain function
Process:
1. Neutralisation, decay, or enzymatic degradation of chemical mediators
→ Stops the inflammatory signal.
- Normalisation of vascular permeability
→ Reduces swelling and fluid exudation. - Cessation of leukocyte emigration
→ Stops further immune cell recruitment. - Apoptosis of leukocytes (especially neutrophils)
→ Controlled cell death prevents further damage. - Clearance of exudate
- Macrophage ingestion of debris, dead cells
- Lymphatic drainage removes excess fluid and proteins
Explain removal (step 1 - recognition)
Removal
1. Recognition
> PRR
- Phagocytes express receptors that sense the presence of microbial pathogens and substances released from dead cells
> Opsonisation
- Opsonization is like preparing a target for easy recognition and elimination by phagocytes.
- Opsonins are molecules that tag pathogens or dead cells so that phagocytes can recognize and eat them more easily.
Opsonins:
1. Bacterial LPS activates complement system that produces C3b with opsonizing properties
2. Antibodies bound to antigens activate complement and also act as opsonin themselves
3. Collectins which bind microbial cell-wall sugar groups
Explain removal (step 2 - activation)
Activation
> Engagement of receptors expressed on leukocyte surfaces by opsonins on microbes and dead cells
> Activation enhances several cellular functions
- Phagocytosis
- Intracellular destruction of phagocytosed microbes and debris
- Release of substances that destroy extracellular microbes and degrade tissue
- Produce cellular mediators to amplify the inflammatory response
Explain the source of plasma and cell derived chemical mediators of inflammation in regulation (step 5)
Regulation
> chemical mediators
1. Cell derived (e.g. leukotrienes, prostaglandin, serotonin, histamine)
- mast cells
- macrophages
- leukocytes
- lymphocytes
- basophils
- platelets
- Plasma-derived (e.g. bradykinin, coagulation/fibrinolysis system)
- Liver
Explain the advantages of plasma derived chemical mediators
🔁 1. Inter-related Enzymatic Cascades
Includes:
Complement system
Kinin system
Coagulation system
Fibrinolytic system
These systems can cross-activate each other, providing redundancy and coordination for a robust inflammatory response.
💤 2. Inactive Precursors in Circulation
Circulate in plasma as inactive zymogens (e.g. pro-enzymes).
Only activated locally at the site of inflammation.
This ensures the response is targeted and spatially restricted, reducing systemic side effects.
✅ 3. Safer Than Pre-formed Active Mediators
Unlike pre-stored cellular mediators (e.g. histamine), plasma mediators only act after activation.
This reduces the risk of inappropriate or excessive inflammation.
📈 4. Amplify the Inflammatory Response
Small initial triggers can lead to large downstream effects through cascading reactions.
E.g., a few complement proteins → large amounts of C3a/C5a → recruitment and activation of leukocytes.
🎛️ 5. More Points for Regulation
Because the cascades involve multiple steps, there are many checkpoints for regulation.
Allows fine-tuning of the response through inhibitors (e.g., C1 inhibitor, antithrombin).
🧪 6. Diverse End Products with Multiple Functions
Each step in a cascade often generates products with different biological effects
This allows the system to coordinate multiple aspects of inflammation: clotting, vessel changes, leukocyte recruitment, etc.
Describe the purpose of histamine, a preformed cell derived chemical mediator of inflammation
Preformed (rapid response) or newly synthesised
Histamine
* Preformed granules
* Released by a variety of stimuli
o Activation of complement
o Physical injury
o Binding of IgE
o Other chemical mediators such as cytokines
* Vascular changes
o Dilation and permeability
Describe the origins and roles of eicosanoids, the arachidonic acid metabolites that are synthesised in response to inflammation
Arachidonic acid metabolites (newly synthesised)
* Mediate most inflammatory steps
o Prostaglandins and leukotrienes
* Short range, act locally, decay spontaneously or enzymatic degradation
> Prostaglandins
o Local effects
Vasodilation
Increase vascular permeability
o Systemic effects
Pain
Hypersensitivity to touch (hyperalgesia)
Fever
Elevation of body temperature
Reset of steady-state temp
>Leukotrienes
o Chemotaxis
o Increase vascular permeability
Describe the clinical and pathogenic effects of systemic inflammation
Systemic effects of inflammation
- Fever
- myalgia (muscle pain)
- Arthralgia (joint pain)
- Anorexia (loss of appetite)
- Somnolence (sleepy)
- Increased heart rate/blood pressure
Acute-phase response (clinical manifestations)
systemic effects of cytokines (IL-I, IL-6 and TNF) induced by inflammatory stimuli
- Microbial products
- Chemical mediators
- Fever
o Elevation of body temp
o Release of pyrogens (molecules that cause fever)
Exogenous (bacterial and viral molecules)
Endogenous pyrogens (cytokines)
o Prostaglandin synthesis
Reset the temp set point in the hypothalamus
o Thought to ward off infection and induce heat shock proteins
o Decreased sweating (redirection of blood flow to deep vascular beds)
o Rigors and chills (temp set point) - Anorexia, somnolence, malaise (action of cytokines on brain)
o Cachexia (wasting due to TNF mediated appetite suppression and mobilisation of fat stores)
o Increased heart rate and blood pressure
Acute phase response – pathologic changes
1. Leucocytosis
- Increased leukocyte count
o Neutrophilia (bacteria0
o Lymphocytosis (viral infection)
o Eosinophilia (hypersensitivities and parasitic infections)
2. Leukopenia
- Decreased leukocyte counts
- Specific infections (Viral/protozoan)
- Overwhelming infection
Explain how the morphology of acute inflammation and how this relates to the pathogenesis of acute inflammation
