Inflammation Flashcards
What are the key signs of inflammation
Calor -heat - increased blood flow Rubor - redness - increased blood flow tumor -swelling Dolor - pain - white cells functio laesa (loss of function)
What is meant by inflammation?
complex reaction in viable vascularised tissues to sublethal cellular injury
What is the general function of inflammation?
Protective response geared towards removing the cause and consequences of the injury
sets stage for potential healing
Outline the general key players in inflammation
Tightly regulated process consisting mainly of leukocyte and vascular responses
Triggered by various cell types and soluble mediators
Which cells are involved in inflammation?
Neutrophils Macrophages Lymphocytes Eosinophils Mast cells
Which mediators are involved in inflammation?
Antibodies
Cytokines
Complement system
Coagulation system
What is acute inflammation?
Rapid non-specific response to cellular injury
Orchestrated by mediators released from injured cells
Leukocyte and vascular response
What is the key aim of acute inflammation and what are the three ways this is achieved?
Rapid delivery of leukocytes and plasma proteins to the site of injury
- Achieved by alteration in the calibre of blood vessels to increase vasodilation
- Structural changes to the microvasculature to allow proteins and leukocytes to leave the circulation (increased vascular permeability)
- Emigration, accumulation and activation of leukocytes at the focus of injury
What are the three basic steps to acute inflammation.
Sublethal injury
Immune cell recruitment
Resolution of acute inflammation
Describe what happens when a sublethal injury occurs
- Inflammatory signals: non-apoptopic cell death
detection of foriegn material - Vasodilators released: histamine and NO
- Vascular changes: Increased permeability, dilation, reduced flow and plasma leakage
How is vascular permeability increased?
Endothelial cells contract: increased interendothelial spacing
Immediate transient response - natural
Histamine and nitric oxide causing cells to contract
Damage to endothelial cells
Why is increased vascular permeability useful?
Rapid movement of antibodies into the site due to slowed blood flow
Recruitment of proteins into tissue increasing activation of immune cells and a source of protein for tissue repair - increased bioavailabilty of substances
Leukocytes form a physical barrier
Leukocyte migration
What is exudate?
The fluid that leaks from the vasculature in acute inflammation (includes fluid, proteins and cells)
What is the purpose of exudate?
Dilute pathogens
Walls off pathogens by separating inflamed tissue from healthy tissue preventing the spread of pathogens
Permits spread of soluble inflammatory mediators to site of injury
Describe the structure of the steady state of skin
Thick epithelial layer, followed by an interstitial layer between epithelial cells and vasculature which is full of immune cells (mast cells and macrophages)
- vasculature contains white blood cells
How can increased permeability be dangerous?
Loss of fluid from blood, reduces volume of blood
particularly dangerous in severe burns where there is a large inflamed area
Which immune cells are important in the initial phase of immune cell recruitment?
Those capable of phagocytosis
predominantly neutrophils but also macrophages
Describe how the immune cells are recruited.
Chemokines produced by activated macrophages at the site of inflammation or help me signals from injured cells called DAMPS, these will diffuse out to form a gradient
Leukocytes ie neutrophils expressing complementary receptors will be attracted and thus migrate to the chemokine source.
What type of cells will an IL-8 chemokine attract?
Neutrophils expressing the CXCR1 and CXCR2 receptors
Name the four basic steps to neutrophil extravasation.
- Chemo-attraction
- Neutrophil rolling
- Tight adhesion
- Transmigration (diapedesis)
Explain chemo-attraction
- Chemo-attraction: cytokines at inflammation site will lead to upregulation of adhesion molecules (selectins P and E) on endothelial surface
Explain neutrophil rolling
Carbohydrate ligands (integrins ie PSGL1) in a low afinity state on neutrophils bind to selectins on the endothelial surface and undergo rolling adhesion This is slowed by sialyl lewis X on neutrophils which bind to selectin
Explain tight adhesion
Chemokines promote switching of integrins on neutrophil to a high affinity state (LFA1 to ICAM1)
This promotes a stronger binding to ligands (ICAM-1) on endothelium
Explain transmigration
Transmigration of the neutrophil through the endothelium wall involves the cytoskeletal re-arrangement and extension of membrane pseudopodia
eventually movement directly into the interstitial mediated by PECAM molecules
What is the function of neutrophils at the site of inflammation?
- Recognise pathogens and necrotic tissue - use of receptors to identify LPS present in bacteria
- Pathogen clearance by phagocytosis and netosis
- cytokine secretion for recruitment and activation of other immune cells
Describe how neutrophils recognize pathogens and necrotic tissue
Toll-like receptors for certain microbial products such as endotoxin
G-protein coupled receptors for certain bacterial peptides (N-formylmethionyl residues)
Describe how neutrophils clear the pathogen
By phagocytosis
- Attachment of phagocyte which engulfs the pathogen (phagosome)
- formation of phagocytic vacuole which joins to a lysosome forming a phagolysosome
- degradation by reactive oxygen species, neutrophils (myleoperoxidase), lysosome, antimicrobial peptides
What are the four ways to resolution of the acute inflammatory response?
- The cause of inflammation is removed
- Macrophages release anti-inflammatory mediators ie lipoxins and clear apoptotic cells
- Inflammatory mediates and neutrophils have a short half life
- Repair/wound healing
Describe what is meant by chronic inflammation
Inflammation of prolonged duration in which inflammation, tissue injury and attempts at tissue repair coexist
What is the time period for chronic inflammation
months to years
What are the main ways chronic inflammation can arise?
- Follows acute inflammation
- low-grade smouldering inflammation (acute inflammation that never resolves)
- Persistent infection
- Prolonged exposure to toxins - either endogenous or exogenous
- autoimmunity (rheumatoid arthritis)
- Foreign body (silica)
What are the main ways chronic inflammation can arise?
- Follows acute inflammation
- low-grade smouldering inflammation (acute inflammation that never resolves)
- Persistent infection
- Prolonged exposure to toxins - either endogenous or exogenous
What are the key features of chronic inflammation?
Lots of T cells and other lymphocytes aswell as a lot of antibody producing B cells
Inflammatory macrophages
No clearance of inflammatory agent, nearby tissue is damaged
concurrent repair processes - fibrosis and angiogenesis
Define what granulomatous inflammation is and give an example of where it is seen.
Distinct pattern of chronic inflammation showing granuloma formation
Seen in TB
What is a granuloma and what is it triggered by?
Aggregate of activated macrophages, in an attempt to eliminate a resistant offending agent
Triggered by strong and specific T-lymphocyte reaction
Describe the histological features of granulomatous inflammation
As the macrophages aggregate they form giant multi-nucleated cells with horse-shoe shaped nuclei
Swirl in centre and giant cells aggregate trying to clear something
What can cause granulomatous inflammation?
infections like TB, Leprosy
Foreign body granuloma
Tumour reactions
Granulomatous diseases ie Sarcoidosis, Crohn’s disease
Suture material - suture granulomas common
Compare acute inflammation to chronic inflammation
Time: acute immediate onset, chronic is delayed
Key lymphocyte: acute neutrophils, chronic monocytes/macrophages
Key mediator: acute histamine release, chronic ongoing cytokine release
acute=necrosis=complete resolution/progression to chronic
chronic=scarring=scarring and loss of function
How do key cellular and molecular processes differ in acute and chronic inflammation?
Acute = Vasodilation, increased vascular permeability, leukocyte response Chronic = Persistent inflammation, ongoing tissue injury, attempts at healing
What are the positive outcomes of inflammation?
Clears offending agents
Cessation of the inflammatory response
Healing of tissue damage with preservation of integrity and function (resolution)
What are the undesireable outcomes of inflammation?
Excessive tissue damage and scarring - can have detrimental effects on adjacent tissue
systemic involvement with multi-organ failure due to septic shock (loss of fluid in a part of the body) or amyloid (binding of compounds to form abnormal proteins)
What are the two ways in which wounds heal?
Resolution or scarring
Describe healing by resolution
Resolution involves regeneration of parenchymal (functional cells) cells with restoration of function
Only occurs if tissue can regenerate and there is little structural damage
Skin and liver can regenerate
Describe healing by scarring
Repair by scarring involves angiogenesis, migration and repair of fibroblasts, scar formation and connective tissue remodelling- molecules seal the piece of injured tissues from the external environment
Occurs when there is significant tissue loss and tissue is unable to regenerate; results in loss of function
When may scars form in response to acute injury, and what are the consequences of these scars
Deep woundsor MI
Parenchymal cell death occurs
Fibrous scar tissue contracts as it matures
If scarring occurs across a joint it can cause poor joint mobility.
Impaired functione.g. fibrous scars in the myocardium after a hear attack, this will impair heart function and may lead to heart failure.
What are the positives and negatives of macrophages in inflammation
Positives: phagocytic so clears apoptotic cell bodies Cytotoxic Can be Anti-inflammatory (IL-10) Wound repair Negative: Cytotoxic Can be inflammatory Pro-fibrotic
What do macrophages do?
Can be recruited as monocytes to the site of inflammation but also form tissue resident
