Chapter 3 Flashcards
Recognition phase of inflammation/immune response
Mechanism involved in identifying abnormal or foreign tissue
T or F, inflammation is non specific
T
Super broad, what does inflammation involve
Changes in vasculature, activation and recruitment of leukocytes to teh site of injury
Purpose of inflammation (4)
- destroy invading particles
- isolate particles or toxins
- restrict area of injury to limit involvement of healthy tissue
- clean up the area for repair
Exogenous factors that can trigger inflammation
Pathogens, temperature changes, physical force, chemicals
Endogenous factors that can trigger inflammation
Self directed immune reactions
Stress
Very broad steps of inflammation
Injured cells release chemical mediators that will increase blood flow to the area
Harmful agents are removed
Phagocytes remove dead cells so repair can start
Chronic inflammation
When inflammation fails to eliminate the thing causing damage, so it stays for a long time
Scarring will take place (fibrosis)
Chronic inflammation is dominated by
Sustained phagocytic activity
Possible routes of inflammation (starting from acute inflammation) (4)
Regeneration
Chronic inflammation
Fibrosis
Abscess
These 4 can then lead to resolution or repair
Acute inflammation characteristics
- Short duration
- lots of neutrophils
- release of mediators that trigger endothelial retraction
- exudation
Exudation
Accusation of fluid in the area causing swelling
Acute inflammation signs (4)
Redness, swelling, pain, heat
Inflammatory response 2 processes
Vascular response
Cellular response
Brief overview of vascular response
One of two processes during inflammation
Involves changes to the endothelium and leads to changes in blood flow
Brief overview of cellular response
One of two inflammation processes
Involved migration and activation of leukocytes
Circulating cells involved in inflammation (6)
Neutrophils
Eosinophils
Basophils
Lymphocytes
Monocytes
Platelets
Circulating proteins involved in inflammation (3)
Clotting factors
Kininogens (for coagulation)
Complement proteins
Role of endothelial and smooth muscle cells in blood vessels in inflammation
Release effectors to trigger coagulation and express adhesion molecules
Connective tissue cells present in inflammation
Macrophages, mast cells fibroblasts
In depth steps of vascular process in inflammation (5 steps)
- Vasoconstriction at local site
- Vasodilation driven by histamine and NO released by tissue and endothelial cells
- Major increase in capillary permeability due to contraction of endothelial cells
- Movement of fluid out of vessels leads to redness and warmth at site
- Increase of blood viscosity of blood due to activation of fibrinogen into fibrin. This slows blood and forms a clot
Not in depth 5 steps of vascular process
Vasoconstriction
2. Vasodilation
3. Exudate into area
4. Redness/swelling/warmth
5. Clot formation
Why does swelling happen during inflammation? why is it helpful
The vascular process leads to vascular permeability. This allows plasma proteins to move into the tissues, bringing fluid with it osmotically
This dilutes harmful substances and bring antibodies and other immune mediating molecules to the site
What causes the pain during inflammation?
Resulting pressure form excess fluid
What factors make blood viscosity increase?
Increase in erythrocyte and platelet concentrations
Increase fibrin polymerization leading to clot formation
Role of endothelial cells in inflammation (5)
Regulate blood flow
- via anticoagulants, VD/VC
Regulate rolling and adhesion of leukocytes (adhesion molecules)
Produce inflammatory mediators
- histamine, NO
Stimulate proliferation of leukocytes
- cytokines
Secrete growth factors that stimuli tissue repair
Granular leukocytes (3)
Neutrophils
Eosinophils
Basophils
Neutrophils
First type of WBC to arrive at site of injury
Carry out first waste of phagocytic activity before macrophages arrive
Eliminate pathogens and damaged cells (phagocytosis)
Die via apoptosis after job is done
Main component of pus
Neutrophils
Eosinophils
Handle allergic and parasitic infections
Basophils
Contain granules that release heparin and histamine
Both mediate inflammatory responses
Non granular leukocytes
Monocytes and lymphocytes
Monocytes
Differentiate into macrophages in the tissues
Second type of cell to arrive at site
Destroy via phagocytosis
Antigen presenting cells
- present antigens to helper T cells
Can survive and replicate in tissues for years if needed
Lymphocytes
B and T cells + subtypes
Initiate active immunity t
Cellular recruitment phases
(4, recruitment of leukocytes to site)
- Marigination and rolling
- Adhesion and extravasation
- Chemotactic migration to site
- Activation and phagocytosis
Margination and rolling
First phase of cellular recruitment
Neutrophils and monocytes adhere to endothelial cells via selectins (type of CAM)
CAMs
Cellular adhesion molecules
Molecules expressed by endothelial cells that let WBCs roll on the walls of vessels
Ex. Selectins
Adhesion and extravasation
Second phase of cellular recruitment
After rolling, WBCs bind to the endothelium (mediated by integrins)
This adhesion causes endothelial cells to retract, allowing the WBC to squeeze through them and emigrate to the extravascular area
Emigration
Movement of WBCs from intravacular space to extra
AKA extravasation
Chemotactic migration
Third phase of cellular recruitment
Leukocytes display chemotaxis once in the tissues
Theses chemicals result in cells migrating towards site of injury
Activation and phagocytosis
Final (4th) stage of cellular recruitment
Neutrophils/macrophages must be activated in the tissues before they work
- recognition of microbes or inflammatory mediators
Once activated they will produce enzymes and ROS to kill pathogens
They also produce cytokines which recruit other cells to amplify inflammatory response
What steps does phagocytosis involve?
Recognition
Engulfment
Digestion
What doe activated WBCs produce? (3)
Hydrolytic enzymes and ROS to kill pathogens
Cytokines to recruit more cells to amplify inflammatory response
Opsonization
Where opsonins (antibodies) bind to and coat a foreign thing so that phagocytes can recognize it and eat it
How do phagocytes phagocytize?
Particle is binded to membrane of phagocyte
Pseudopods engulf it, forming a phagosome
Fuses with a lysosome, forming a phagolysosome
Digested by lysosomes
What happens when phagocytosis leads to death of the phagocyte?
Results in cell lysis and release of digestive enzymes and ROS
Key mechanism of inflammatory injury as it damages healthy nearby tissue and can lead to chronic inflammation
If a lot of phagocytes die, pus forms
Serous inflammation
Formation of protein rich fluids called serous exudate
Characteristic of mild/early inflammation
Purulent or suppurative inflammation
Exudate that contains lots of neutrophils, fluid, debris or bacteria
Has purulent exudate which is pus, can be yellow, white or green
Has localized or diffuse forms
Purulent inflammation: localized vs diffuse forms
Localized:
- abscess develops due to inability to clear debris
- pus walled off by collagen and need surgical draining
Diffuse (cellulitis)
- when purulent inflammation spreads through tissue. Usually due to bacterial infections, treated with antibiotics
Hemorrhagic inflammation
Severe
Where blood leaks out of vessels into tissue forming hemorrhagic exudate or transudate
Transudate
Low protein fluid that forms when where is minor increase in vascular permeability (so little protein gets through)
Can happen during hemorrhaging inflammation
Classes of acute inflammation
Serous inflammation
Purulent/suppurative
- locatives/diffuse
Hemorrhagic
How are the vascular and cellular phases of inflammation told to happen?
They are signalled by inflammatory mediators
Inflammatory mediators can be: (2)
Cell derived or plasma derived
3 examples of plasma derived inflammatory mediators
The compliment system
Coagulation system
Kinin system
The complement system
Cascade of 20+ proteins from the liver
Can be activated via 3 pathways
- classic
- alternative
- lectin pathway
All of these pathways end in formation of C3 convertase which is converts C3 into C3a and b
C3A and C3B functions
A: binds to leukocytes and leads and causes inflammation and recruitment of more leukocytes
B: acts an a opsonin by binding to pathogens for phagocytosis
Coagulation system
Cascade of plasma proteins that contribute in clotting
Has extrinsic and intrinsic pathways
In the coagulation system, how is each pathway triggered?
Intrinsic
- initiated by platelets binding the surface receptors on collagen
Extrinsic
- triggered by damage to the blood vessel
Coagulation common pathway
Both extrinsic and intrinsic pathways lead to the formation of prothrombinase
This plus calcium converts prothrombin into thrombin
Thrombin plus calcium turns fibrinogen into fibrin
Thrombin activates factor 13 which strengthens fibrin threads
Coagulation pathway: extrinsic
Tissue trauma causes release of tissue factor
This plus calcium activates factor X
Factor X plus calcium = prothrombinase
Coagulation pathway: intrinsic
Damaged endothelial cells expose collagen fibres
Platelets + thrombin = platelet phospholipids
Activated factor 12 due to damaged endothelial cells + platelet phospholipids + activated factor X
Factor X plus calcium = prothrombinase
What does thrombin do?
Catalyzes fibrinogen into fibrin
Promotes chemokine production and expression of inflammatory mediators
Kinin system
Small peptide molecules called kinins which cause vasodilation
Intertwined with coagulation system
How is teh Kinin system triggered?
By tissue injury
Exposure of the extra cellular matrix to blood causes activation of factor 12
Kinin system cascade
Factor 12 in blood is activated by exposure to ECM
Activated factor 12 leads to activation of kallikrein
Activates kallidin into bradykinin
What does bradykinin do?
Strong inflammatory mediator that causes vasodilation, increased permeability, and pain
All three systems (complement, coagulation, and Kinin) are activated by, and promote ________
Inflammation
Positive feedback loops
Cell derived inflammatory mediators
Can either be stores prior to inflammation or made on demand
Can be preformed (histamines, serotonin) or newly made (prostaglandins, leukotrienes)
Histamine
Stored and produced in mast cells
Very important mediator in inflammation
Released in response to heat, physical trauma, and complement activation
Main effect: increased vascular permeability and vasodilation
Serotonin effect in inflammation
Vasodilation and increased permeability
Eicosanoids
Family of compound derived form phospholipids (such as arachidonic acid)
Rapidly metabolized, short duration of action
Major eicosanoid groups (5)
Prostaglandins
Prastacyclins
Thromboxanes
Leukotreines
HETE
Pathways in the production of eicosanoids (2)
Cyclooxygenase
- production of prostaglandins
Lipoxygenase
- - production of leukotreines
Major anti eicosanoid drugs are:
Corticosteroids
Inhibit initial step of arachidonic acid production, blocking production of prostaglandins and leukotrienes
Major side effect: immunosuppression
Inhibitors of cyclooxygenase pathway (stops prostaglandins, prostacyclin, and thromboxanes)
NSAIDS
Expression patterns of cycloxygenase enzymes
COX 1 and COX 2
1: expressed in GI tract and platelets
2: expressed in response to inflammatory stimuli, responsible for pain and swelling
Systemic effects of inflammation
Lymph involvement
Fever, pain
Blood changes
Inflammatory mediators by effect: vasodilation
NO, Prostaglandins
Inflammatory mediators by effect: fever
Prostaglandins
Tissue necrosis factor
Interleukin 1 and 6
Inflammatory mediators by effect: Increased vascular permeability
Histamine, serotonin, bradykinin
Leukotrienes
Inflammatory mediators by effect: pain
Bradykinin, PGs
Inflammatory mediators by effect: Chemotaxis
Cytokines
Inflammatory mediators by effect: tissue damage
Neutrophils and macrophage lysosomal enzymes
ROS
NO
Possible outcomes of acute inflammation
Abscess forms
Progression to chronic
Resolution
- tissue goes back to normal
Repair
- healing by scarring or fibrosis
Abscess
Pus appearing in an acute or chronic infection
Associated with tissue destruction and swelling
Usually result of progenitor organism
Differences between acute and chronic inflammation
Acute
- not specific
- neutrophil dominant
- causes redness, edema, and increase blood flow
Chronic
- specific
- macrophage dominant
- causes fibrosis, angiogenesis, and tissue destruction
Simple resolution
When the damaging thing is destroyed without injury to normal tissue
Things quickly return to normal
Pro inflammatory mediators subside while anti inflammatory mediators increase
Regeneration
Dead cells are replaces with new ones in tissues that can do so
Replacement
Replacement of tissue by collagen if it can’t regenerate
Can also be a different type of tissue
Organization
Removal of debris, exudate, and clotted blood by macrophages
Epithelialization
Regeneration of epithelial tissue to protect exposed areas
Collagenation
Laying down of collagen to form a fibrous scar, providing strength to the area
Cicatrization
Formation of mature scar which is less elastic and vascular than younger scar
Histiocytes
Dominant in chronic inflammation
Eg. kupffer cells
Cytokines storm
Sudden system wide release of cytokines in response to infection that results in massive changed in vascular permeability and VD
Drop in BP and shock, can kill you
Leukocytosis
Increase in leukocytes in the blood
Used to diagnose (different types of WBCs can mean different things
Healing by first intention
When there is a clean wound
- no tissue loss
- edged can be brought together
- forms a thin white line scar
Healing by second intention
Considerable tissue damage or loss
- larger wounds caused by burns, necrosis, etc
- take longer to remove debris
- significant inflammation
- wound is no sutured but kept clean
- results in large scar and deformation or surrounding tissue
Healing by third intention
Wound is cleaned but left open
- used when tissue grafts are used
- leaving wound open promotes inflammation and thus removal of debris and pathogens
Keloids
Excessive scar tissue that forms a mass that protrudes beyond borders of injury site
Corticosteroids can be used to slow progression
Contracture
Tissue contraction that continues after closure
Can lead to deformation
Constriction and stenosis
Where contraction of a scar occurs around lumen of a tubular organ, it can lead to narrowing of the lumen (stenosis)
Adhesions
As repair happens, tissues can fuse together abnormally. Common in abdomen (loops of intestine)
Dehiscence
Rupture and opening of a closed wound
- caused by inadequate collagen, circulation, new trauma, etc
Evisceration
Any injury in which the viscera are exposed and out of position form abdominal area
Macrophage function
Produce ROS
Cause influx of other cells
Cause fibroblast proliferation
Phagocytosis
Plasma cells
Antibody producing cells
Fully differentiated B cells
Fibrinosis inflammation
Serous fluid plus plasma proteins like fibrinogen
Seen in infections of the pleural cavity
Ulcer
Local defect or excavation of the surface of an organ or tissue. Presence of necrotic tissue on or near a surface
Factors needed for resolution
Removal of the infectious agent
Regenerative ability if cells have been destroyed
Intact stromal framework
Organization is done mainly by:
Fibroblasts
Components needed for repair
Angiogenesis
Migration of fibroblasts
Deposition of ECM
Fistula
Tearing of tissue that connects two compartments
Common in pregnancy
Tearing of tissue between vagina and rectum
Lymphadenopathy
Swollen and tender lymph nodes
Lymphangitis
Inflammation of a lymph vessel
Lymphadenitis
Inflammation of a lymph node
What mediates pain?
Bradykinin, histamine, serotonin
