Inflammation Part 1

specific vs non-specific inflammation

• specific means immune response

• non-specific means inflammatory response

order of lines of defense

1. natural barriers

2. inflammation

3. immunity

mechanical natural barriers

• getting rid of pathogens through “mechanical” ways

• sloughing, coughing, vomiting, urinating, cilia in respiratory tract

• includes low skin temps to discourage bacteria growth

chemical natural barriers

• mucous, perspiration, saliva, tears, earwax that trap and kill microorganisms

humoral meaning

blood/plasma components

what are the three major events of inflammation

1. increased metabolic rate

2. dilation of blood vessels

3. increased capillary permeability

why is there an increased metabolic rate during inflammation

• increase in cell activity to fight

• increase in our heat production, oxygen and glucose consumption, waste production

methods of mediation of inflammation

1. mast cell degranulation

2. activation of 3 plasma protein systems

3. release of cell derived mediators

where can mast cells be found

in connective tissue:

• Close to a blood vessel

• Along lung and GI tract mucosa

• Dermis of the skin

how do mast cells mediate inflammation

• they are filled with pre-formed granules and when activated, release the contents like histamine, serotonin, enzymes into circulation to start inflammation effects immediately

• create lipid mediators of inflammation from cell membrane

• stimulate cytokyine and chemokine synthesis

• releases a factor which attracts eosinphils (wbc) to site of inflammation

what do mast cells do in allergic reactions

they bind to one of the immune globulins IgE to trigger the release of histamine and vasoactive substances

plasma protein systems

1. Complement system (cell lysis)

2. Clotting (formation of fibrin clots)

3. Kinin (production of bradykinin)

how does complement system mediate inflammation

Mediates inflammation by causing vasodilation, increasing vascular permeability and enhancing activity of phagocytes

what are the three avenues in which the complement system can be activated

1. classical pathway

2. lectin pathway

3. alternative pathway

classical pathway of activation of complement system

activated by antibodies

lectin pathway of complement system

• Activated by bacterial carbohydrates

• No antibodies required

alternative pathway of complement system

• Activated by gram negative bacterial and fungal cell wall polysaccharides

• No antibodies required

what are the most important proteins in the complement system

C3 and C5

functions of c3 and c5

• opsonins (tagging bacteria for destruction), chemotactic factors and anaphylatoxins

• Chemotactic factors draw inflammatory mediators to the site of injury as needed

• Anaphylatoxins cause rapid degranulation of mast cells to increase the inflammatory response

endpoint of complement system

• Membrane Attack Complex (MAC)

• Its job is to create holes in pathogen membranes to make the cells explode (cell lysis)

how is the clotting system initially activated

• through intrinsic and extrinisc pathways converging

• factor 12a Hageman in intrinsic pathway

• factor X (blood clotting protein) becomes factor Xa

primary goal of clotting system

produce a fibrous clot which stops bleeding and prevents the spread of infection by trapping the pathogen and retaining it at the site of inflammation

what happens in the kinin system

• bradykinin is generated from plasma proteins called “kininogens” through the action fo enzymes called kallikrein

primary goal of kinin system

to produce bradykinin which is similar to histamine (increase vasodilation, vascular permeability, stimulates pain) although it has shorter effects

what does the hageman factor activate

1. clotting cascade

2. fibrinolytic system through the conversion of plasminogen into plasmin

3. kinin system through activation of prekalilikrein

4. C1 and the complement cascade

histamine

• Binds to H1 receptors on endothelial cells which increases blood flow

• Increases vascular permeability by causing the retraction of endothelial cells

• Stimulates adherence of leukocytes to the endothelium

• Increases GI motility

• Does not mediate opsonization

negative consequences of histamine

causes smooth muscle constriction of the bronchioles which makes it difficult to breathe

serotonin effects in inflammation

Causes smooth muscle contraction, small blood vessel dilation and increased vascular permeability

Lysosomal Enzymes role in inflammation

Able to fuse with phagosomes in phagocytes to destroy pathogens

Arachidonic Metabolites role in inflammation

• Fatty acids in cell membrane

• Released from mast cells to initiate reactions that lead to the production of other inflammatory mediators

prostaglandin role in inflammation

• Made from arachidonic acid metabolites to induce inflammation

• Promote vasodilation, bronchoconstriction, increase neutrophil chemotaxis, cause pain

thromoxane A2 role in inflammation

Produced by platelets at the site of injury to promote platelet aggregation, bronchoconstriction and vasoconstriction

leukotrienes role in inflammation

• Similar to histamine

• Increase vascular permeability, induce smooth muscle contraction, constrict pulmonary airways

• Prolong inflammatory response

platelet activating factor role in inflammation

• Induces platelet aggregation

• Activates neutrophils

nitric oxide role in inflammation

• Produced by endothelial cells and cause smooth muscle relaxation

• Antagonize platelet actions

• Reduces leukocyte recruitment

oxygen free radicals role in inflammation

• At low levels, they increase the expression of cytokines and endothelial adhesion molecules

• At high levels, they damage the endothelium and lead to increased permeability

phases of inflammation

1. vascular

2. cellular

vascular phase of inflammation process

1. brief vasoconstriction followed by vasodilation

2. biochemical mediators cause retraction of endothelial cells to increase vascular permeability

cellular phase of inflammation

movement of leukocytes from the blood into the tissues

1. margination

2. adhesion

3. transmigration

4. chemotaxis

leukocyte margination

Leukocytes move along endothelial wall

leukocyte adhesion

• Leukocytes slow down to to slower velocity of blood flow

• Leukocytes stick to the endothelium with the help of adhesion molecules/ICAMs

leukocyte transmigration

Leukocytes cross the blood vessel wall through junctions into the tissues

leukocyte chemotaxis

• Leukocytes move towards the site of injury

• They move in response to a chemical gradient caused by chemokines, bacterial and cellular debris and protein fragments

• Chemotactic factors also caused movement of cells

phagocytosis process

1. phagocyte recruitment and activation to the site of injury

2. phagocytes extend pseudopods that surround and engulf the pathogen

3. fusion with lysosome to form a phagolysosome

4. phagolysosome which will release its enzymes and oxygen radicals to breakdown the pathogen

what does alpha 1 antitripysin do

inhibits destructive effects of toxic lysosomal contents to protect healthy tissues from destructive effects

what is edema in inflammation caused by

• Caused by vasodilation and increased movement of blood to the site of injury

• Increased capillary permeability

• Leakage of proteins and cells out of the endothelial wall taking water with it

what is redness in inflammation caused by

Caused by vasodilation and increased movement of blood to the site of injury

what is pain in inflammation caused by

• Caused by increased fluid in tissues

• Prostaglandins acting directly on nerve endings

• End product of kinin system and bradykinin

what is pus in inflammation caused by

dead neutrophils becoming exudate

what is clot in inflammation caused by

clotting cascade which acts to keep pathogens and microbes in the area of injury

causes of chronic inflammation (characteristics of these microbes/pathogens)

• microbes have waxy cell walls that resist phagocytosis which cause inflammation to persist

• they release toxins upon their death that damage tissues

Granulomatous inflammation

Type of chronic inflammation where the immune system forms granulomas (calcified fibrous deposits) to wall of microbes inside

how does atherosclerosis begin (endthoelial injury → platelets and monocytes)

• Injury or elevated cholesterol damages the endothelium to produce less antithrombotic (prevent blood clot) and vasodilating substances

• Platelets adhere and aggregate at the injured area

• Injured endothelium increases adhesion molecule expression

• Monocytes attach to the endothelium

how are free radicals released in the subendothelial layer

• after monocytes move into the subendotheliail layer, they develop into macrophages and release free radicals and other inflammatory substances

LDL oxidation in atherosclerosis

• LDL accumulates beneath the endothelium

• Free radicals cause LDL to become oxidized

• Oxidized LDL triggers further inflammation

Foam cell formation in atherosclerosis

Macrophages consume oxidized LDL to become foam cells

what happens after foam cell formation in atherosclerosis

• Foam cells and phagocytes release cytokines, mediators and growth factors which promotes further inflammation and endothelial injury

• Smooth muscle cells migrate and proliferate to make artery wall narrower