Module 2: Inflammation Flashcards
What are the two types of immune defenses?
1) innate– fast but non-specific and is both the 1st and 2nd line of defense
2) adaptive– slow but very specific and is the 3rd line of defense
Describe the innate immune response
fast, non-specific to particular antigens, ex. mucous production
Describe the adaptive immune response
very specific response to a very specific antigen– this response is developing between 6 months and 2 years of age
What causes acute inflammation?
any breach of body defenses results in an immediate, localized response to damage (acute inflammation)
if the issue is not resolved then it may result in chronic inflammation
What is the difference between first line of defense and second line of defense?
first line– physical barriers, biochemical barriers, and normal microbiome
second line– antimicrobial substances (ex. cytokines), and immune cellular defenses (innate WBC functions such as apoptosis), inflammatory response, and fever
Describe the third line of defense (adaptive immunity)
2 lymphocyte types with difference mechanisms of destroying the antigen
1) humoral (antibody mediated) immunity (B lymphocytes)
2) cell mediated immunity (T lymphocytes)
What is humoral immunity?
also called antibody mediated immunity, part of the third line of defense
B lymphocytes–> differentiate into plasma cells–> production of specific antibody/immunoglobulin which binds to and results in destruction of antigen
What is cell mediated immunity
part of the third line of defense
T lymphocytes–> production of antigen specific helper T cells (stimulate other T and B cells) and cytotoxic T cells–> bind to and stimulate apoptotic destruction of antigen containing cell
What are the two key features of adaptive immunity?
1) specificity– each B or T cell responds to one specific type of antigen
2) immunological memory– each B or T cell remembers the antigen and subsequent re-exposure elicits a rapid response (so fast that no symptoms of illness should appear)
What is included in the microscopic blood vessels?
arterioles, capillaries, and venules
Describe the arterioles
they vasoconstrict and vasodilate to control local capillary bed blood flow to tissues
contain smooth muscle
Describe the capillaries
sit of nutrient and gas exchange
do NOT contain smooth muscle
Describe the venules
direct blood flow away from capillary bed
contain smooth muscle
What do precapillary sphincters do?
they are rings of smooth muscle that contract and relax to regulate blood flow into the capillary bed
What are cytokines?
the nervous system of the WBCs
What are chemokines?
the attract WBCs to a site
What happens if too much histamine is released? not enough?
too much causes hypersensitivity and not enough causes immunodeficiency
What are the 5 signs of inflammation?
redness, heat, swelling, pain, and loss of function
Define inflammation
the tissue response to injury or infection– occurs in vascularized tissue
Define inflammatory response
describes how various tissues react to injury or infection that causes tissue damage– non-specific, rapid response of injured tissue to any causative (etiological) agent of tissue damage
What are the purposes of the inflammatory response?
-limit further tissue damage
-prevent spread of injurious agent/infection
-stimulate adaptive immune response
-begin wound healing process
What effect does stromal tissue have on tissue damage?
-triggers the inflammatory response
-increases vascular permeability
-vasodilation
-fibroblasts secrete protein fibers called collagen
-mast cells secrete histamine and heparin
What does heparin do?
prevents blood clotting
What effect does parenchymal tissue have at the tissue damage site?
-may be damaged and need to be replaced
-do not directly cause the inflammatory response
What are the two patterns of inflammatory response and what determine which one it is?
1) acute inflammatory response
2) chronic inflammatory response
based on the duration of the response and the specific WBCs present in the lesion
Describe acute inflammation
-innate, immediate tissue response to injury
-main chemical mediator is histamine
-tries to limit the damage and prevent scarring
-promotes wound healing by bringing in nutrients and removing debris
-predominant immune cells: mast cells, neutrophils and macrophages (order is important)
Describe chronic inflammation
-innate and adaptive, prolonged tissue reaction to continued injury or persistent infection
-main chemical mediator is histamine
-still trying to limit the damage and promote wound healing, but scarring is probable
-predominant immune cells: macrophages, lymphocytes, and mast cells (order is important)
What are the 3 possible results of wound healing?
1) resolution– damaged cells recover
2) regeneration– replacement by same type of cell
3) repair– scarring occurs
What are the major WBCs involved in the acute inflammatory response and what do they do?
Mast cells– secrete histamine (major proinflammatory chemical mediator)
Neutrophils– phagocytic; first responders to tissue distress
Macrophages– phagocytic; clean up cellular debris (slow to get to the site)
What are the 3 types of plasma protein systems responses for the acute inflammatory response?
1) complement
2) coagulation
3) kinin cascades
These promote inflammation and blood clotting when needed
What are the 3 major components of the acute inflammatory response?
1) the vascular response
2) the cellular response
3) the plasma protein systems response
These are caused by the release of histamine and are all proinflammatory!
Describe the vascular response of the acute inflammatory response
the immediate histamine-mediated response by the microvascular endothelial and smooth muscle cells within the wound site; it will increase blood flow into the injured tissue and increase vascular permeability
Describe the cellular response of the acute inflammatory response
includes all 3 types of blood cells– WBCs, platelets, and RBCs as they respond to injured tissue and increase vascular permeability
Describe the plasma protein systems response of the acute inflammatory response
includes a variety of biochemical responses to injury; these proinflammatory proteins are part of the acute phase proteins, they are transported in the blood plasma to the injury site, where they act as proinflammatory mediators (complement system, coagulation system, and kinin system)
Where are mast cells located?
in the connective tissue surrounding the microvasculature
Where are histamine receptors located?
endothelial cells and smooth muscle cells
What are the effects of histamine release on the microvasculature during an inflammatory response?
(very long answer)
tissue damage stimulates mast cells to rapidly “degranulate” ie. release histamine from storage in cytoplasmic vesicles. Histamine bind to histamine receptors on vascular endothelial and smooth muscle cells causing specific independent responses and 3 things happen:
1) the arteriolar and precapillary sphincter smooth muscle cells-> histamine stimulates vascular smooth muscle cells to relax-> arteriole vasodilation and opens precapillary sphincters-> increased rate of blood flow to cap. bed
2) venular endothelium-> histamine stimulates endothelial cells to contract-> ‘myo’endothelial contraction creates inter-endothelial cell gaps-> increased vascular permeability
3) venular endothelium-> histamine also stimulates endothelial cells to decrease production of anti-endothelial cells and infiltrate the wound site-> promotes leukocyte infiltration and clot formation
What type of cells produce histamine?
Mast cells– innate tissue immune cells that recognize and respond to tissue ‘distress’ signals by secreting histamine and other proinflammatory mediators, including heparin
What are the cell characteristics of mast cells?
-derived from pluripotent stem cells in red bone marrow
-reside in connective tissue (stromal immune surveillance cells)
-recognize tissue damage, microbial invasion
Describe the 2 mechanisms in which mast cells release proinflammatory mediators
1) mast cell degranulation
-immediate release of mediators
-the mediators are made in advance and stored in vesicles within the mast cell (look granular)
-histamine
-other proinflammatory mediators (chemotactic factors and cytokines)
2) mast cell synthesis
-slower release of newly synthesized mediators
-includes cell membrane components of damaged mast cells
-chemokines (made by any cell that is dying)
Does histamine cause pain?
not directly, it can stimulate the edema that pushed on nerve endings causing them to be compressed or irritated, it is said to elicit all 5 signs, even if one is an indirect effect
What is histamine?
a proinflammatory vasoactive amine that affects the microvasculature and other target tissue
basically means a chemical that causes a vessel to act/respond to stimulation by that chemical (vasoactive) and this chemical contains an NH2 (amine) group
What are the 2 types of histamine receptors?
H1 receptors: proinflammatory effects on target cells
-endothelial cells
-vascular smooth muscle (makes it relax)
-bronchiole smooth muscle (makes this muscle constrict)
-immune cells (WBCs)
H2 receptors: anti-inflammatory effects on target cells
-gastric parietal (HCL secreting) cells (increase secretion)
-immune cells (WBCs)
Antihistamines are antagonists to which type of histamine receptor?
H1
What are some examples of drugs that are anti-inflammatory?
antihistamines, glucocorticoids, and NSAIDs
What is the purpose of plasma?
-lubes the endothelial cells
-stops unwanted blood clots
-the reason cells go down the center of the vessel
Describe blood flow in a normal (uninjured) blood vessel
-axial streaming of blood cells
-plasma in the plasmatic zone
-minimal gaps between endothelial cells
-endothelial cells secrete anti-adhesion chemicals
Describe blood flow in acutely inflamed blood vessels
-histamine mediated ‘myo’endothelial cell contraction-> interendothelial cell gaps which then lead to:
-increased venular permeability
-endothelial cell secretion of pro-adhesion chemicals (CAMS)
-blood cells enter plasmatic zone-> adhere to endothelium-> enter wound site
results in edema
What causes the 5 cardinal signs of inflammation?
histamine induced microvascular endothelial and smooth muscle responses to tissue damage
What two types of microvascular cells respond to histamine?
endothelial and muscle cells
What are the effects of histamine on the microvasculature?
a) in arterioles there is vasodilation (red and hot)
b) in capillaries there is passive vasodilation (red and hot)
c) in venules there is permeability (pain, edema, and loss of function)
Why is the vascular response important during acute inflammation?
bring nutrients, protein, WBCs
What are the clinical manifestations of the vascular response to histamine?
red, heat, swelling, pain, and loss of function
What is actin’s normal function and which cells express actin?
motility and every cell if needed but normally endothelial and during inflammation WBCs
Define edema
the excessive accumulation of fluid within the interstitial spaces
a tissue with excess fluid is called edematous
How much excess tissue fluid needs to be present before the swelling becomes ‘noticeable’?
around 30%
What is third spacing?
the fluid has entered the tissue (generalized edema)
What is ascites?
abdominal-pelvic cavity has fluid
What are the two types of edematous fluid?
1) transudate
2) exudate
-two subtypes are fluid exudate and cellular exudate
What are the 4 pressures that control normal capillary exchange? and do they promote filtration or reabsorption?
1) Blood/capillary Hydrostatic Pressure (BHP)- filtration, pushes fluid out of capillaries into tissue
2) Interstitial Fluid Osmotic (Oncotic) Pressure (IFOP)- filtration
3) Blood/Capillary Osmotic (Oncotic) Pressure (BCOP)- reabsorption, pulls fluid into the capillaries from the tissue
4) Interstitial Fluid Hydrostatic Pressure (IFHP)- reabsorption
How do the pressures change during an inflammatory response?
interstitial fluid pressure increases
What is the difference between osmotic and oncotic pressure?
osmotic pressure is the pressure exerted by chemicals found in a solution that pull/attract water towards them (promote osmosis)– does not require a living membrane to occur
oncotic pressure is the osmotic pressure exerted by colloids in a biological solution, such as blood plasma or interstitial fluid
the terms are often used interchangeably
Where is the highest fluid pressure and where is the lowest?
highest is in the arterioles and lowest is in the venules
Describe the lymphatic system briefly
-drains into veins in neck
-absorbs excess interstitial fluid
-picks up 3L of fluid daily
-damaged in people with severe edema
When the Blood Hydrostatic Pressure (BHP) goes up what happens?
arteriole vasodilation increases blood flow into capillary bed
When the interstitial fluid osmotic pressure (IFOP) increases what happens?
presence of microbial proteins, cell debris, and proinflammatory mediators is tissue fluid
When the blood colloid osmotic pressure (BCOP) decreases what happens?
normal: minimal effect
if liver disease: hypoalbuminemia
if kidney disease: proteinuria
If the interstitial fluid hydrostatic pressure (IFHP) increases what happens?
arteriole vasodilation– increased venular vascular permeability and decreased lymphatic drainage
Which direction is fluid movement during filtration? reabsorption?
filtration– into tissue
reabsorption– into blood
What is the main difference between transudate and exudate?
timing of production and specific chemistry
Describe transudate
-immediate, excess watery tissue fluid
-essentially the same chemical composition as normal tissue fluid produced during capillary exchange-> water, salts, electrolytes
-result of increased local blood flow and increased local blood hydrostatic pressure (due to arterial vasodilation)
-comes out of dilated arterioles
Describe exudate– two types
1) fluid exudate– excess tissue fluid rich in plasma proteins (help with innate and adaptive immune response)
2) cellular exudate– includes the WBCs that infiltrate the injury site (in clotting, also includes platelets and RBCs)
-takes longer to begin as it requires myoendothelial contraction to occur
-comes out of venules because they have the biggest gaps
Which form of edematous fluid is first to an injury site?
transudate
What type of pressure causes edema?
an increase in Blood Hydrostatic Pressure (BHP) and decreased Blood Colloid Osmotic Pressure (BCOP)
When a tissue is injured, 2 smooth muscle vascular effects occur in quick succession, what are they?
arteriolar vasospasm– immediate but brief contraction of vascular smooth muscle in response to sympathetic nervous system release of norepinephrine or epinephrine
arteriolar vasodilation– histamine mediated smooth muscle relaxation causing redness and heat
Which cells promote inflammation?
-mast cells
-basophils
-neutrophils
Which cells act as phagocytes?
-neutrophils
-macrophages
-dendritic cells
-B lymphocytes-> plasma cells
-NK cells
-eosinophils
Which cells induce apoptosis?
-NK cells
-eosinophils
-cytotoxic T lymphocytes
Which cell boosts innate and adaptive responses?
helper T cells
What is pus made of?
dead and dying WBCs (mainly neutrophils), dead and dying body cells, and dead and dying bacteria
What do WBCs respond to during acute inflammation
1) increased vascular permeability– causing slower local venule blood flow which allows WBCs to enter plasmatic zone and eventually produce cellular exudate
2) injured cell distress signals– cytokines and chemokines that promote WBC chemotaxis and infiltration into injury site
Define chemotaxis
-the directional movement of leukocytes in response to a chemical gradient
-common chemotactic agents: cell debris, microbes, proinflammatory chemokines and cytokines
Define margination
also called pavementation
mechanism by which WBCs move to outer margins of vessel (into plasmatic zone) tumble along the endothelium, and adhere to endothelium
Define diapedesis
mechanism by which WBC squeeze into wound site through the inter-endothelial gaps
What are CAMS?
cell adhesion molecules made by phagocytes in response to microbial chemicals or damaged cell products; help with WBC motility and with phagocytosis of the correct cell
What type of exudate is resultant of leukocyte infiltration/emigration into the wound site?
cellular
Describe the platelet response during acute inflammation
occurs if the blood vessel wall is damaged during injury– are you bleeding?
respond to:
1) loss of endothelial cells due to blood vessel wall damage-> allows platelet-collagen interaction-> platelet activation occurs
2) slower/more focused viscous blood flow-> resulting from increased vascular permeability during inflammatory response-> allow platelets to adhere to damaged blood vessel wall
What is included in platelet activation?
platelet adherence-> platelet release reaction-> platelet plug formation-> hemostasis (meaning stop the bleeding)
What are the components of a blood clot?
platelets, sticky fibrin threads and trapped RBCs
Which NSAID blocks thromboxane A2 activity (during blood clotting)?
ASA/ aspirin–> blood thinner
What do RBCs respond to during acute inflammation?
1) slower local blood flow
2) platelet activation
What is included in RBC activation during acute inflammation?
RBC adherence-> rouleaux formation (stacked like coins)-> followed by extravasation (more bleeding).. bleeding into tissue-> RBCs help form extravascular blood clot
What is the purpose of RBC response during acute inflammation?
to help limit blood loss by strengthening and stabilizing blood clot
Describe the general characteristics of the plasma protein systems
-produced by liver and/or WBCs
-most produced in advance; circulate in blood plasma as inactive proenzymes
-peak activity 10-40 hours post tissue damage
-act as proinflammatory mediators
they work by:
tissue damage-> inactive circulating proenzymes-> convert to active enzymes-> cascade of enzyme activity-> proinflammatory response
Describe the complement system
-innate immune response
-series of 9 plasma proteins; called C1-C9
-come from the liver
What is the mechanism of action of the complement system?
3 pathways of complement protein activation
1) classical pathway– antibody present
2) lectin pathway– bacteria present
3) alternative pathway– bacteria or yeast present
this is all you need to know about these pathways, they do not need to be memorized
What are the functions of the complement system?
physiological effects of complement protein activation:
-form membrane attack complexes (MAC)
-act as opsonins
-act as leukocyte chemotactic agents
-act as anaphylatoxins
-attract antibodies to wound site
end result of complement activation is promote inflammation and help destroy pathogens
Define opsonization (opsonin)
‘to make tasty’ this complement protein will sugar coat the surface of the antigen to be phagocytized helping to attract phagocytes and make the process of phagocytosis more efficient
What is the coagulation (blood clotting) system mechanism of action?
1) endothelial damage occurs-> platelet-collagen interaction in damaged blood vessel-> platelet activation
2) blood flow stasis-> platelet activation
-platelet activation leads to sequential activation of clotting factors of the coagulation cascade-> sticky fibrin threads form and RBCs and platelets get caught to form a blood clot
What are the 2 routes to activation of the clotting cascade?
1) extrinsic– triggered by outside damage
-more common
-tissue damage stimulates parenchymal and stromal cells to release tissue factor
2) intrinsic– 99% pathology (starts in vessel)
-endothelial damage-> platelet-collagen interaction
-platelet activation
Which cells break up bruises?
macrophages
What gives a bruise its colour?
the breakdown of hemoglobin
What enzyme breaks up blood clots by breaking down the fibrin threads?
plasmin– this process is called clot dissolution
