Cell injury/death, inflammation/immune response Flashcards
Etiology
Cause
Pathogenesis
sequence of cellular or tissue events in response to the etiologic agent, from initial stimulus to the ultimate expression of the disease
morphologic changes
structural alterations in cells and organs of the body that characterize the disease or are diagnostic of the etiologic process
clinical significance
functional consequences of the morphologic changes
Cell Adaptations
hypertrophy: increase in size (Myocardial fibers)
atrophy: shrink or decrease in size
hyperplasia: increase in number of cells/increased rate of cellular division
Metaplasia: reversible change in which one adult cell type is replaced by another adult cell type (can result in neoplasia)
Cell Injury
cause and types
Causes: hypoxia, physical or chemical agents and drugs, infectious agents, immunological reactions, genetic defects, nutritional imbalance, aging
Types: metaplasia (reversible)
(irreversible): disturbance in cell membrane and cell wall, mitochondrial dysfunction
What happens to the cell when it is injured and dies?
-ATP depletion
-decreased ATP synthesis
anaerobic metabolism and acidosis
-number of Na/K pumps decrease
more Na in cell pulls more water
-dilation of ER causes decreased protein synthesis
-accumulation of free radicals with not enough
antioxidants
-Ca influxes which causes more damage and can
cause cell death/catabalize cell membrane
-Mitochondrial damage and loss of membrane integrity results in cell death
-apoptosis (cell eats self)
What are the two types of cell death?
Necrosis:
- abnormal and not regulated
- loss of membrane integrity
- stimulates inflammation (increase leukocytes triggers lysosomes to release enzymes for digestion of cell substances)
Apoptosis:
- normal and regulated (can become abnormal in disease)
- physiological (cell no longer needed) or pathological (cell is threat)
- contents of cell shrink, membrane remains intact and does not stimulate inflammation
What are free radicals?
chemicals that have a single unpaired electron in outer orbit (unstable!)
produced during mitochondrial respiration
cause cell damage by reacting with nucleic acids, and other cellular proteins and lipids
What are the two types of oxygen derived free radicals?
- Reactive Oxygen Intermediates (ROS)
types: O2 superoxide H2O2 hydrogen peroxide
OH hydroxyl radical
produced in phagocytic leukocytes and mainly macrophages and neutrophils - Nitric oxide Intermediates (NOS)
produced by leukocytes and other cells
types: physiological {endothelial (eNOS), neuronal (nNOS),}
non-physiological {inducible (iNOS)}
What free radical causes the most damage?
OH hydroxyl radical
What regulates free radicals?
Antioxidants (physiological substances that protect the body against damage from chemical reactions caused by free radicals)
Function: bind to and break down free radicals by enzymes
block formation
bind to ions to take free radicals away and out of cell
repair damage they cause in cell
Types of Antioxidants
catalase (enzyme from perioxisomes organelle) superoxide dismutase (SOD) gluthione peroxidase (GSH) CoQ10 Vitamin E, A, C, and Beta-Carotene Synthetic Ones (dopamine and other meds)
What is oxidative stress?
When the balance between free radicals and antioxidants is off and there is more free radicals than antioxidants.
Which NOS is the problem/causes damage?
iNOS is induced by inflammatory cytokines and responsible for production of NO in inflammatory reactions; also critical for wound healing
What is the role of the three NOS?
vascular smooth muscle relaxation, vasodilation
antagonizes platelet activation
decreases leukocyte recruitment
microbicidal agent
Where do all blood cells reside?
stem cell pool, bone marrow pool, and peripheral blood pool
What does thrombopoieten do?
peptide produced by liver, kidneys, skeletal muscle, and marrow stoma responsible for clotting factors and platelet production
The myeloid stem cells differentiate into…
interluekins, erythrocytes, thrombocytes, monocytes, myelocyte (granulocyte: neutrophils, eosinophils, basophils)
What cells differentiate from lymphoid stem cells?
plasma cell, NK cells, T cells, B cells
What are the types of leukocytes?
- monocytes (immature)
produced in bone marrow
mature to macrophages in tissue
they are the FRONT LINE because they are already there and they are more efficient than neutrophils (they can phagocytize up to a 100 before they die)
replicate in tissue
secrete inflammatory metabolites and cytokines
are antigen presenting cells to activate T and B cells - Neutrophils
mature in bone marrow (mature-segs/immature-band cells)
LARGEST IN CIRCULATION
digest 3-20 before dying
release cytokines and facilitate inflammation - eosinophils (destroy parasites, involved in allergic responses)
- basophils (release histamine, leukotrienes, prostaglandins and platelet activating factor in inflammation; have IgE receptors and bind to IgE antibody; ALLERGY)
What are the types of lymphocytes?
- T cells (most abundant)
originate in bone marrow&mature within the thymus
reside in the T cell zones of lymphoid tissue and spleen
Types: T helper, T cytotoxic, T suppresser, MEMORY cells - B cells
mature in bone marrow and reside in lymph nodes of cortex and medulla and spleen B zones
antigen receptors on surface: IgM and IgD
Types: plasma cell and MEMORY - NK cells
target virus, malignant, and other mutant cells
secrete cytokines to activate macrophages and T cells
NO MEMORY
How many antigens can a T cell react with?
one
What is a plasma cell?
a B cell that has been activated to secrete antibodies (immunoglobulins IgG, A, E)
How do NK cells work?
release enzymes: perforin and granzyme onto surface of cell
perforin disrupts membrane and
granzyme enters cell and causes lysis
or it will attach it’s Fas receptor to a Fas ligand on the target cell and this causes: Fas-Fas ligand Mediated Apoptosis
What is margination and rolling referring to? And why is “adhesion” necessary?
Leukocytes travel the vascular system rapidly so in inflammation they have to be slowed down and brought to source of trauma or infection.
- Margination: during inflammation slowing of the circulation causes leukocyte accumulation at the periphery of the vessel
- Rolling: leukocytes tumble along the endothelial surface to escape vascular system.
endothelial selectins E and P and leukocytes selectin L adhere to slow them down and attach to the endothelium to keep them at the site of trauma/inflammation
What are chemical mediators of inflammation?
HISTAMINE: released by mast cells, basophils and platelets
action: vasodilation and increase permeability
SEROTONIN: produced by rap he nuclei or dorsal horns of spinal cord and released by platelets
action: causes vasoconstriction and increased vascular permeability
ARACHIDONIC ACID (AA): when cells are injured the phospholipid bilayer of membrane is released and converted to AA
PLATELET ACTIVATING FACTOR: released from platelets, basophils, mast cell, and leukocytes and endothelial cells to produce platelet aggregation, vasodilation, bronchoconstriction, and increased leukocyte adhesion to endothelium, chemotaxis and degranulation
CYTOKINES: proteins that transmit messages between cells
they are produced by many cell types (interleukins, TNFs, interferons, colony stimulating factors)
*stimulate growth, differentiation, and function of leukocytes and immune cells; involved in systemic inflammatory response and *Stimulates HEMAtopoeisis
ROS and NITRIC OXIDE (NO): macrophages, neutrophils release it and use it as cytotoxic agent for killing microbes and tumor cells; relaxes vessels(vasodilation);
NEUROPEPTIDES: example Substance P neurotransmitter: pain impulse regulates vessel tone and moderate permeability
What are the two pathways of metabolism of AA?
- Cyclooxygenase pathway
COX1 and COX2 enzymes act on AA to produce prostaglandins(vasodilation, involved in pain, fever and hyperalgesia) and prostacyclin (vasodilation, inhibits platelet aggregation) and thromboxane (vasoconstriction and promotes platelet aggregation) - Lipoxygenase pathway
enzymes act on AA to produce leukotrienes (increase vascular permeability, promote neutrophil recruitment and adhesion, vasoconstrictor, bronchospasm) and lipoxins (vasodilation, inhibit neutrophil recruitment)
What drugs inhibit the two pathways of metabolism of AA?
ASA, NSAIDS, COX2 inhibitors and steroids inhibit cyclooxygenase pathway.
steroids also inhibit lipoxygenase pathway
What does the plasma-derived interrelated systems of inflammation mean?
*already circulating plasma proteins are involved and when each system is activated then they all are activated
What are the plasma-derived interrelated systems of inflammation?
- Complement System
routes of activation:
-classic pathway: C1 (activated by antigen-antibody complexes)
-lectin pathway: C1 (activated by plasma lectin that binds to carbs on surface of microbes)
-alternative pathway: C3 (activated by microbial products, plasmin, and lysosomes released by neutrophils) - Kinin System
- triggered when XII is activated =XIIa
- results in release of bradykinin (vasodilation, increase permeability, extravascular smooth muscle contraction, acts with prostaglandins to INDUCE pain)
- reactivates XII to allow for amplification of initial stimulus
- activates the fibrinolytic cascade which produces plasmin (***PLASMIN activates complement system) - Clotting System
intrinsic pathway (*XII activated when it touches exposed collagen)
extrinsic pathway
Which is the most critical component of the Complement system that needs to be activated?
- ***C3 is the MOST critical: cleavage occurs by three pathways (classic, alternative, and lectin pathway)
- stimulates neutrophils and macrophages to phagocytize
- C3a, 4a and 5a activate mast cells, basophils to stimulate histamine and serotonin release
- C5 activates AA metabolism lipoxygenase, and C5a is a chemotactic agent for leukocytes
- C6-9 form membrane attack complex (MAC)
What is the MAC?
creates pores in the membrane and influx of water and ions destroy cell
What factor is needed to activate C3 of complement system?
XII activates when it touches exposed collagen; it then activates the fibrinolytic system to produce plasmin and plasmin activates C3
What are the 2 primary types of T helper cells?
TH1 and TH2
What protein markers are on T helper cells?
CD3 and CD4
What is major histocompatability complex?
MHC is a cluster of genes located on chromosome 6; expressed on surface of cells;
MHC1 antigens: found on surface of all nucleated cells
MHC2 antigens: found mostly on B cells, macrophages, dendrite cells
**the point is to tell self cells from foreign invaders by the sequence of peptides
Which class of MHC does the cytotoxic T cells kill?
MHC1 only
What is the point of the suppressor T cell?
limits binding of antigen to lymphocyte and helps prevent excessive response
How many signals do T cells and B cells need to activate?
2
How many classes of immunoglobins of B lymphocytes are there?
5 clases (IgM, IgG, IgA, IgE, IgD)
What is an antibody?
it is secreted into body fluids to bind to antigens to create a ANTIGEN-ANTIBODY COMPLEX; inactivates or neutralizes bacterial toxins, virus
act as opsinin by marking it for attack
What activates the complement system?
plasmin, IgG antigen complex
How does the B cell become a plasma cell that secretes IgG, IgA, or IgE antibodies specific to the organism?
after the helper T cell has been activated and differentiates, Th2 secretes IL 4 and IL 5
IL 4 and 5 modify B cell to become plasma cell
