Inflammation Flashcards
What is Inflammation?
a protective response to tissue insult or injury aimed at eliminating the cause of injury, remove damaged cells and initiate repair
How can Inflammation Damage Healthy Tissue?
strong inflammatory reaction, prolonged reaction, when response is inappropriate
5 SIGNS OF INFLAMMATION (CDFRT) - call doctor for reaction time
Calor - heat
Dolor - pain
Function Laesa - loss of fucntion
Rubor - redness/erythema
Tumor - swelling/oedema
What are the 5 R’s
Recognition of Injurious Stimulus
Recruitment of Leukocytes
Removal of Agent causing Injury
Regulation of Response
Resolution of Response and Repair
PRR
How is injurious Stimulus Recognised? (Recognition)
phagocytes, dendritic cells, epithelial cells express PRR
- recognise and bind to specific molecular patterns
- fast response
the specificity of the PRR’s are genome encoded
John Hunter (1800’s) said inflammation is not a disease, but a response to tissue damage
How does Circulatory Plasma Proteins and Vasculature have a part in Inflammatory Response? (Recognition)
CPP = clotting systems, complement, cells of immune system
V = blood system and its endothelium
What can a LOT of tissue trauma lead to?
Necrosis, Apoptosis, Ischemia, Chemical Insults
What is Tissue Necrosis?
Loss of membrane integrity and release of cellular content into extracellular space
How can Inflammation be Triggered? (4)
Infectious agents
foreign bodies
immune reactions
trauma - physical, thermal, irradiation
What is Cell Apoptosis, how does it Happen?
programmed cell death
= DNA is packaged and content released into membrane bound parcels and then engulfed by phagocytes
- induced by nK cells and cytotoxic T cells
What is Ischemia?
loss of oxygen - leads to necrotic cell death
What happens if the Stimulus isn’t Removed? Or if Acute Response Cannot be Resolved.
the injury persists
chronic inflammation
Two Types of Inflammation
Acute and Chronic
Describe Acute Inflammation. Onset, Duration, Infiltrating Cells, Injury and Local/Systemic Signs
Onset - quick
Duration - short
Infiltrating Cells - PMNS and macrophages
Injury = mild and self-limiting
Local/Systemic Signs = clear and prominent
Describe Chronic Inflammation. Onset, Duration, Infiltrating Cells, Injury and Local/Systemic Signs
Onset - slow
Duration - months-years
Infiltrating Cells = macrophage and lymphocytes
Injury = Severe and gets worse
Local/Systemic Signs - subtle and less prominent
What are the Vascular Changes? (Recognition)
Vasodilation, Permeability, Endothelial Cell Activation
What are the Cellular Events? (Recognition)
Leukocyte recruitment of PMN’s
Leukocytes infiltrate tissues
What is the Most Important PRR and Where is it Found?
What Structures can they be?
TLR - Toll Like Receptors
on extracellular surfaces or facing inwards on endosome
Heterodimeric or Homodimeric
TLR-1,2,4,5,6 are on Extracellular Surfaces, What are their Functions? (Recognition)
TLR-1 - hetero - recognise triacyl lipopeptides
TLR-2 - hetero - recognise di/triacyl lipopeptides and lipopolysaccharide
TL-4 - recognise lipopolysaccharide
TLR-5 - recognise flagellin
TLR-6 - hetero - recongise diacyl lipopeptides
TLR-3,7,9 are on Endosomal Surfaces, What are their Functions? (Recognition)
3 - detect double stranded RNA
7 - detect single stranded RNA
9 - bind to unmethylated CpG DNA (cytosine-guanine nucleotide)
What are Lectin Like Receptors? (Recognition)
a type of PRR
- binds to pathogen derived sugars
What is the Cytosol?
the matrix of the cytoplasm
What is a NLR and it’s function? (Recognition)
Nod-Like Receptor
recognises lipids, bacterial peptiglycans and components of dead cells
What is a RIG-I and it’s Function? (Recognition)
Retonoic Acid-Inducible Gene I
recognise the 5-triphosphate from viral RNA in the cytoplasm
- eukaryotic gets modified so it doesn’t get recognised
What is a NLRP3 inflammasome? (Recognition)
recognises dead cell components, crystal and some pathogenic bacterial components by activating zymogen form of caspase form
What does Caspase do when Activated? (Recognition)
activates a protease
cuts, cleaves and activates precursor form of IL-1-beta
this is secreted = acute inflammation
What are the Key Cells of Recognition? (8) TLRLMNNN
PMNS, macrophages, lymphocytes, TLR, Lectin Like Receptors, NLR, RIG-I and NLRP3 Inflammasome
What is Vasodilation? (5)
widening of blood vessels
more blood flow
less pressure
less speed
area = warm and red
What Happens with Vascular Permeability?
- Endothelium is leaky and gaps between cells increase
- plasma fluid and proteins enter and leave tissues
area = swollen, oedema
What Fluid leaves the Cells when there is Vascular Permeability? What is the Function of this Fluid?
Serum Exudate - GCF is an exudate
- to deliver components to the necessary site
What is Endothelial Cell Activation? (5)
- selectin (adhesion molecules) receptors are expressed on cell surface
- leukocytes with wbc bind via their ligand - (sialyl-lewis-x-modified glycoprotein) to receptor
= white blood cells bind to inside of tissue wall - leukocytes pass through endothelial layer
- enter tissues
How is Vascular Dilation induced?
by cytokines IL-1, TNF, Histamines and Kinins
STEPS OF RECRUITING LEUKOCYTES (5)
- margination
- rolling
- stable adhesion
- transmigration
- chemotaxis
How does Margination work? (Recruiting Leukocytes)
- vasodilation
- slower blood flow
- WBC accumulate on periphery of inside of vessels
What Travels Faster in the Blood Vessels, WBC or RBC?
RBC - they are smaller
What is Rolling? (Recruiting Leukocytes) (5)
- pro-inflam cytokines and histamine activate endothelial cells close to site of inflammation
- adhesion molecules selectins
- interact with molecule on WBC = sialyl-lewis x-modified glycoprotein
= weak interactions - repeatedly broken and remade as leukocyte rolls along blood vessel wall
What is Stable Adhesion (Recruiting Leukocytes) (4) What Molecule Helps the Leukocyte pass through?
- when leukocytes are activated, there are changes in the integrins
= the change = higher affinity binding site to cell adhesion molecules - cell stop rolling and come to a stop
- PECAM-1 helps leukocyte pass through vascular endothelial layer
What is Transmigration? (Recruiting Leukocytes)
- leukocytes secrete enzymes e.g. collagenases
- create hole in basement membrane
- enzyme passes through
- exit blood vessel
- enter tissue
What is Chemotaxis? (Recruiting Leukocytes)
leukocyte follows chemical gradient
What is Arachidonic Acid?
intracellular pro-inflammatory mediators with a short half-life
What can Arachidonic Acid be Metabolised into? (2)
cylooxygenase and 5-lipoxygenase
Cycloxygenase is metabolised from Arachidonic Acid, What can it Create? (2)
prostaglandins and thromboxane
What are Prostaglandins made from and their function? (3)
made from cycloxygenase
- increase sensitivity to pain
- clotting
What Medicines are Prostaglandins inhibited by? (3)
aspirin, ibuprofen and neproxin
5-Lipooxygenase is Metabolised from Arachidonic Acid, What can it Create?
Leukotrienes and Lypoxins
Leukotrienes is made from 5-Lipooxygenase, What is its Function?
Chemoxtaxis and Vascular Permeability
How do you Remove the Agent Causing Injury? (4)
- Phagocytosis
- Secrete Microbial Substances into Extracellular Space
- Pro-Inflam Cytokines
- Release Extracellular Traps
What are the steps of Phagocytosis? (Removal) (7)
- Recognition by phagocytic receptor
- Engulf pathogen and other inflam materials
- plasma membrane invaginate
- Fuse with lysosome
- in the same vesicular space
- degradation
- respiratory burst
Recognition from Phagocytosis may also be via Opsonins, What are these? (Removal)
complement components such as antibodies
- increase the efficiency of recognition
What Cells Partake in Phagocytosis? (Removal)
macrophage, neutrophils and dendritic cells
What is Respiratory Burst in Phagocytosis? (Removal)
the rapid production of reactive oxygen species
How does Respiratory Burst Work during Phagocytosis? (3)
- NADPH converted into O2 by phagocyte oxidase
- oxygen into hydrogen peroxide or hyperchlorid by MPO myeloperoxidase
- super oxide + nitric oxide = peroxynitrite
What is the Effect of Respiratory Burst? (Removal)
toxic products - cause damage to DNA, membranes and proteins
What Microbicidal Substances are released into the Extracellular Space? (Removal) (7)
Antimicrobial peptides, reactive oxygen, nitrogen species, lysosomal enzymes, chemokine, cytokines, NETosis
The Function of Microbicidal Substances (Removal) one side effect also.
Toxic to kill and destroy pathogens but can cause bystander damage to host cells
What do Neutrophils contain that cause Damage? (Removal)
azurophilic granules store microbicidal substances
- blue in colour
How can Neutrophils cause Damage? (Removal)
azurophilic granules store microbicidal substances
- blue in colour
What are the Neutrophilic Enzymes? (3) (Removal)
neutrophil elastase, proteinase 3, cathepsin g
= Proteolytic enzymes to engulf materials
Function of Pro-Inflam Cytokines. (Removal)
amplify the response
Define NETosis (Removal)
the release of extracellular traps by neutrophils
What is the Function of Netosis? (Removal)
bind debris, clear up and get rid of pathogen
What are the ‘nets’ made from in Netosis? (Removal)
dense net of fibres made up of nucleosomal DNA and histone proteins attached to microbicidal molecules
- contain high concentration of LL37 and Proteinase 3
How are NET’s formed? (Removal) (4)
- neutrophil decondenses chromatin
- nuclear envelope integrity is lost
- DNA unwound and uncoiled
- DNA escapes nucleus using PAD4 and content of granules mix (microbicidal substances)
For DNA to escape the nucleus during NETosis, PAD4 is necessary, what is this and its function? (Removal)
peptidyl arginine deaminase 4
converts arginine and methyl arginine amino acids in the histone proteins into citrulline amino acid
= positive into neutral electrostatic charge
Orally, where can large quantities of NET’s be found? (Removal)
in the gingival crevicular fluid of periodontitis
What are the 2 Key Regulators of the Regulation of the Response?
Chemical Mediators
Chemokines
What are the Chemical Mediators used in Regulation?
Arachidonic Metabolites
Complement Proteins
Coagulation Protiens
Cytokines and Chemokines
Lysosomal Enzymes
Lysosomal Enzymes
NO
ROS
Kinins
Vasoactive Amines
What are the Chemical Mediators used in Regulation? (10)
Arachidonic Metabolites
Complement Proteins
ROS
Lysosomal Enzymes
Coagulation Proteins
NO
Kinins
Cytokines and Chemokines
Vasoactive Amines
Examples and Function of Vasoactive Amines - Chemical Mediator (2) (2) (Regulation)
- Histamines and Seratonins
- vasodilation and vascular permeability
Examples and Function of Arachidonic Metabolites - Chemical Mediator (2) (2) (Regulation)
- Prostaglandins and Leukotrienes
- Vascular reactions and chemotaxis
Examples and Functions of Cytokines and Chemokines - Chemical Mediators (4, 2) (1,2) (Regulation)
- TNF, IL1, IL6, CXCL8
- leukocyte recruitment and endothelial activation
- Hepatocytes
- active liver cells that stimulate synthesis of acute phase proteins
Examples and Function of Lysosomal Enzymes - Chemical Mediator (4) (2) (Regulation)
- Neutrophil Elastase, Proteinase 3, Collagenase, Cathepsin C
- microbicidal and tissue injury
Function of NO and ROS - Chemical Mediator (3) (Regulation)
(nitrous oxide and reactive oxygen species)
- vasodilation, microbicidal, tissue injury
Function of Complement Proteins - Chemical Mediator (3) (Regulation)
Leukocyte chemotaxis, oponisation, MAC
Function of Coagulation Proteins - Chemical Mediator (3) (Regulation)
Triggered by F7
- endothelial activation
- leukocyte recruitment
Function of Kinins - Chemical Mediator (2,2) (Regulation)
Protelytic cleavage - activate precursor
Vascular Reactions and Pain
What are Cytokines also called? (Regulation)
Endogenous Pyrogens - made in the body to raise temp
What Chemokines are Present in the Liver? (4) (Regulation)
Serum Amyloid Protein
Fibrinogen
C-reactive protein
Mannose Binding Lectin
What does C-reactive protein do in the liver? (Regulation) (4)
a pentraxin - class of PRR that acts an opsonin
- activates classical complement pathway
- C1 interacts with pathogen surface = C3 Convertase
- levels increase with infection
- used as a marker as it binds directly to bacterial and fungal surfaces
What does MBL do in the Liver? (Regulation)
Peforms opsonin activation, complement activation and lectin pathway
- binds carb to lectin = C3 Convertase
What is the Function of Chemokines in other parts of the body: liver, bone marrow, hypothalamus, fat muscle cells, dendritic cells
Liver
- Serum Amyloid Protein
- Fibrinogen
- C-Reactive Protein = acts as an opsonin and activates classical complement pathway, used as a marker if someone has infection
- MBL - opsonin activation, complement activation and lectin pathway
Bone Marrow Epithelium
- Leucocytosis = increase production and release of neutrophils into bloodstream
Hypothalamus
- increase body temp and antigen processing
- decrease viral and bacterial replication
- increase specific immune response
Fat Muscle Cells
- mobilise protein and energy cells
Dendritic Cells
- TNF-a stimulates migration to lymph nodes and maturation
How was Resolution of Response Previously Understood to How it is Now?
if signal is removed, duration of response will stop BUT resolution is active and an regulated process
What molecules are needed in Resolution?
- immunoresolvants
IL-10
Maresins
Protectins
Resolvins
- inhibit leukocyte infiltration
Lipoxins
- inhibit neutrophil adhesion and chemotaxis to endothelial surfaces
= less recruitment
= prevent continuation of inflam response
After Resolution, Homeostasis can be Returned. Describe Homeostasis.
- few infiltrating homeostasis
- cells maintain health and remove debris
What Molecules are No Longer Needed During Resolution?
pro-inflam cytokines and chemokines
histamines
prostaglandins
leukotrienes
thromboxanes
Define Chronic Inflammation
A prolonged duration of the inflammatory response, when regulation and resolution fail.
What is the Dominant Cell of Chronic Inflammation?
Macrophages
- can be pro or anti inflammatory
In Chronic Inflam, Describe the Pro-Inflam Macrophage (5)
Classically Activated Macrophage
- macrophage activated by the cytokins interferon gamma signal produced from the TH1 T-Helper Cell
- Phagocytosis
- Secretion of lysosomal enzymes
- Secrete pro-inflam cytokines
TNF, IL-1, IL-2, IL-6, IL-23 - presents antigen to T cells
= repeats
In Chronic Inflam, Describe the Anti-Inflam Macrophage.
Alternatively Activated Macrophage
- macrophage activated from signals from IL-4 or IL-13 from TH2 cells
- promote repair and anti-inflamm
- release IL-10 and TGF-β
What is the Effect of Chronic Inflammation?
- tissue injury
- fibrosis - fibroblasts new connective tissue
- angiogenesis - new blood vessels
What is the Effect of New Tissue During Chronic Inflammation?
non-specialised
the function of the tissue can be lost and lead to further damage
Describe Characteristics of Chronic Inflam.
- Mononuclear Cells Inflitrate
- Tissue Destruction
- Granulomatous Tissue
- Fibrosis
What Oral Infection can have Both Acute and Chronic Inflammation?
Dental Abscess
- chronic as fibrous tissue and monocytes cells surround the walls but it is a neutrophil dominated response, making it acute
Chronic Inflammation can be Present from the Onset with this Disease.
Rheumatoid Arthiritis
Diseases Linked To Periodontitis - an Inflam Disease
Inflammation induced Pregnancy Complication
Atherosclerosis
Diabetes
How is Diabetes Linked to Inflammatory Periodontitis?
- raised inflammation activates and increases the expression of proteins suppressing insulin-signalling pathways
- raised insulin resistance
= harder to control blood sugar levels
Diabetes can also affect proteins in our tissue and collagen turnover
P Gingivalis is a key pathogen, what does it have similar activity to?
PAD 4
- an enzyme that functions in NETosis
research to see if generated autoantigens can trigger autoimmunity
