Exam II Flashcards
An impulse in one neuron that spreads to another neuron via a pathway of low electrical resistance is known as
Electrical transmission
- highly synchronized
- fast
- -mammalian neurons, gap junctions (in non-neural cells like glia, epithelial, muscle cells, liver and glandular)
Transmission of impulses via synapse (site where information is transmitted from one cell to another). It allows integration.
Chemical transmission
- no continuity (b/t cytoplasm of pre-synaptic terminal and post-synaptic neuron)
- synaptic clefts separate cells
True/False: In chemical transmission, information is transmitted across the synaptic cleft via neurotransmitter. The NT is released form the pre-synaptic terminal and binds to receptors on the post-synaptic terminal.
True
*voltage gated Ca2+ channels at the end of the pre-synaptic neuron
A receptor that allows ions into the cells directly (via ion channels)
IOnotropic receptor
*fast response
A receptor that uses a G protein to activate an ion channel and allow ions into the cell, or that uses a G protein to create a signalling cascade
Metabotropic receptor
- G-protein gated ion channel
- second messengers
*slow response
The major mechanism for clearance of most transmitters is:
a. enzymatic degradation
b. reuptake by pre-synaptic processes
c. internalization by post-synaptic process
d. uptake by glial cells
e. diffusion
Answer: Re-uptake by presynaptic processes
Drugs can affect synaptses at a variety of sites and in a variety of ways including:
- Release NT from vesicles
- Produce more or less NT
- Block re-uptake of NT
- Block receptors
Drugs that block NT reuptake increase the concentration and duration of action of the NT in the synaptic cleft. What are examples of these drugs?
- Fluoxetine
- -SSRI (anti-depressant)
- -blocks reabsorption of serotonin - Cocaine
- -blocks the DAT (dopamine transporter)
- -prevents DA reuptake
* hyperactive locomotive patterns
*expand availability of the NT already present in the synaptic cleft (that can bind to post-synaptic receptors)
Drugs can affect synaptses at a variety of sites and in a variety of ways including:
- Release NT from vesicles
- Produce more or less NT
- Block re-uptake of NT
- Block receptors
Which drug performs all 4 of these effects?
Amphetamine
- Enters cell
- -passive diffusion or membrane bound DAT (reuptake transporters) - Redistribution of DA from vesicles into cytosol (VMAT-2)
- Mobilies stored NT from storage vesicles
- -increases concentration of NT in cytosol - Blocks pre-synaptic re-uptake of DA by DAT
- -inhibits MAO
GABA acts as the principal inhibitory NT. It aids in controlling neuronal hyperactivity by inhibiting
Glutamate (excitatory)
–excessive glutamate = seizures (exotocicity; neuronal death)
GABA is inhibited by what enzyme?
GABA transaminase
*inhibition of GABA transaminase by Valproic acid *anti-convulsant) = increased GABA in synaptic cleft
It Has 3 major receptors:
- GABA A
- GABA B
- GABA C
GABA A and C are both ionotropic receptors, allowing the flow of ____ ions into the neuron.
Chloride ions flow into the neuron
- hyperpolarization
- dec. action potentials
- Benzodiazapene (BZD)
It Has 3 major receptors:
- GABA A
- GABA B
- GABA C
GABA B is a metabotropic receptor which uses a G-protein to activate what kind of ion channel?
K+ (flow out of cell)
- hyperpolarizes cell (more neg)
- Flumazenil, Phenobarbital, ETOH
NOTE: all GABA respond to fear, anxiety and convulsions
In addition to having binding sites, GABA has allosteric binding sites for other substances known as GABA modulators.
GABA modulators can increase or decrease the action of GABA, but have no effect in the absence of GABA.
What are examples of positive modulators? Negative?
- Positive:
- -BZD (treats anxiety, fear, epilepsy) (benzodiazapene binding site)
- -barbiturates - Negative:
- -Flumazenil (convulsant)
- –reverses effects of BZD; non-competitive antagonist (binds GABA antagonist site)
—Anti-epileptics which inhibit Na2+ current (e.g. phenobarbital)
–Anti-epileptics which enhance GABA-ergic inhibition (benzos, phenobarbital)
–ETOH (barbiturate binding site)
Glutamate is the principal excitatory NT. It has two types of Ioniotropic receptors:
- AMPA (Na2+)
- NMDA (Na2+/Ca2+)
These receptors are located on the dendritic spines and play a major role in learning and memory via _____
Long Term Synaptic Potentiation (LTP)
- when glutamate binds these receptors = channels open
- memory = at synaptic level
WHat are the steps in NT release?
- Depolarization (action potential) in presynaptic cell. Results in calcium channels opening at axon terminal.
- Calcium influx into presynaptic cell occurs
- Calcium mobilizes synaptic vesicles
- Synaptic vesicles fuse to presynaptic terminal button membrane
- Exocytosis occurs: process of vesicles fusing to plasma membrane and opening to release their content into extracellular space.
- Neurotransmitter substance diffuses across the synaptic cleft
- Neurotransmitter attaches to receptor sites on post synaptic membrane
- Neurotransmitter affects the chemical gates of the postsynaptic membrane, changing membrane permeability.
Long Term Synaptic Potentiation (LTP) is a principal form of synaptic plasticity in the mammalian brain, through to underlie learning and memory.
During development there is a refinement of synaptic connections (Hebbian synaptic modification).
The following are necessary for successful initiation of LTP and for the promotion of memory consolidation and distribution:
- _______: functional memory formation and retrieval
- ______: synapses work as a functional group
- ______: is synthesized and inserted into the post-synaptic membrane of dendrites
- Synchrony
- -functional memory formation and retrieval - Stimuli repetition
- -synapses work as a functional group - AMPA-R is synthesized and inserted into post-synaptic membrane (of dendrites)
- -phosphorylated for inc. glutamate response
A physical trace of a memory in the brain
Engram
- activation by stimulus
- neuronal assembly
- rehearsal/reactivation
- LTP (Hebbian synaptic modification)
- strengthened connections
True/False: Memories are stored in the interconnected neurons (neuronal ensemble) from areas involved in sensation and perception
True
True/False: Formation of an engram involves strengthening synaptic connections (LTP) between populations of neurons, neuronal ensembles.
True
- The nerves that innervate muscle fibers
- Comprises a single motor neuron and the muscle fibers it innervates
- Synapses between a motor neuron and a muscle fiber is known as a
- motor neurons
- motor unit
- -facial expressions, quadriceps in running - Neuromuscular junction (NMJ)
Ach is formed from acetyl CoA and choline via choline acetyltransferase. It is stored in vesicles w/ ATP and proteoglycan for subsequent release.
On stimulation, the entire vesicle is released into the synaptic cleft. The smallest possible amount of Ach that can be released is the one quantum (amt. within one synaptic vesicle).
How is acetylcholine broken down?
Acetylcholinesterase (Ache) in the synapse
*choline transported back into axon terminal to be re-used
There are 2 major subtypes of Nicotinic Acetylcholine receptors: muscle-types and neuronal-type.
_______ type receptors are present at the NMJ. It is a complex of 5 subunits of four proteins (alpha, beta, gamma, delta)
Muscle type receptors
2a, 1 B, 1 d
There are 2 major subtypes of Nicotinic Acetylcholine receptors: muscle-types and neuronal-type.
______ type receptors are a complex of five subunits of 2 proteins (alpha and beta). They can form combinations of 12 different nicotinic receptors
Neuronal nAchR
- Ligand-gated ion channel
- K+ out
Describe the process of SK muscle contraction via Ach stimulation
*Synaptic Transmission Slide 36
- An action potential in a motor neuron is propagated to the terminal button.
- The presence of an action potential in the terminal button triggers the opening of the voltage-dated Ca++2 channels and the subsequent entry of Ca++2 into the terminal button (Ca++2 uptake)
- Ca++2 triggers the release of the acetylcholine by exocytosis from a portion of the vesicles.
- Acetylcholine diffuses across the space separating the nerve and the muscle cell membrane (synaptic cleft).
- Acetylcholine binds to the nicotinic acetylcholine receptors opening the ligand-ion channel leading to a relatively large movement of Na into the muscle cell compared to a smaller movement of K outward.
- The result is an end plate potential. Local current flow occurs between the depolarized end plate and the adjacent membrane.
- This local current flow opens voltage-gated Na channels in the adjacent membrane.
- The resultant Na entry reduces the potential from cero to threshold, initiating an action potential, which is propagated throughout the muscle fiber. (-80 to 0mV)
- Acetylcholine is subsequently destroyed by acetylcholinesterase, an enzyme located on the motor end plate membrane, terminating the muscle cell response.
An autoimmune disorder characterized by Abs that interact with the post-synaptic nAChR, leading to increased turnover of receptors and damage to the post-synaptic membrane.
**Fewer functional receptors
Myasthenia Gravis
- send receptors to the grave
- Increasing fatigue
NOTE: once receptors are reduced to 30%, failure of neuromuscular transmission and presence of symptomatic weakness
What are the primary characteristics of Myasthenia Gravis?
–Hallmark: Weakness/increasing fatigue
- ocular muscle weaknes
- double vision
- ptosis
- CN VIII
- motor: bilateral weakness/paralysis
______ is a disease characterized by Abs against the voltage gated Calcium channels which reduce ACh release.
These lowered levels of Ach are not sufficient for normal muscle contractions, leading to muscle weakness.
Lamert-Eaton Myasthenic Syndrome
- small cell lung cancer
- lung cancer
- abnormal pupillary response
- dry mouth
- areflexia
This is the most common and most severe acute paralytic neuropathy distinguished by rapidly damaged peripheral nerves (loss of myelin sheath).
It is typically a post-infectious disorder associated with Campylobacter jejuni.
Guillain-Barre
- glial/axonal membrane injury w/ consequent conduction failure
- symmetric ascending weakness + areflexia
- autonomic dysfunction (sinus tachycardia)
- parasthesisa (numbness/tingling)
One of the most common inherited neurological disorders. It is an X-linked inherited neuropathy caused by mutations in genes CMT1A and PMP22 (myelin sheath)
Charcot-Marie-Tooth disease
- peripheral neuropathy
- leg weakness and atrophy in 2nd decade of life
*inverted champagne bottle due to loss of muscle bulk
For differential diagnosis of Charcot Marie Tooth Disease, gene mutation is seen in
HINT1: axonal neuropathy
RAB7A: hereditary sensory and autonomic neuropathy
MFN2: axonal neuropathy (postural tremor and optic atrophy)
Which of the following is a mechanism by which cells communicate?
a. peptides/proteins
b. amines (NE, E)
c. steroid hormones (aldosterone/estrogen)
d. small molecules (aa, nt, ions)
e. gases (NO)
Answer: all
What are the primary leukocytes associated with acute inflammation?
Neutrophils
True/False: Cytokines have multiple effects depending on numerous factors including inflammatory context, target organ, presence of receptors, presence of other cytokines
True
_________ describes the response of vascularized tissues to infections and/or damage that brings cells and molecules of host defense from the circulation to the needed site
Inflammation
Which of the following is/are fundamental properties of the inflammatory response?
a. vessels (vascular)
b. leukocytes (cellular)
c. associated w/ tissue damage
d. local and systemic effects
e. mediated by soluble factors released from cells and present as plasma proteins
f. acute and chronic inflammation have different mechanisms and cellular players
Answer: all of the above
Vascular component: inc. vascular permeability, vasodilation, endothelial injury
Leukocytes: WBC’s
–acute vs. chronic
Acute inflammation includes which of the following?
a. fast (minutes, hours)
b. mainly neutrophils
c. prominent local/systemic signs
d. severe and progressive
Answer: A-C
*mild and self-limited
Which of the following describes chronic inflammation?
a. neutrophils
b. slow, days
c. severe and progressive
d. fewer local and systemic signs
Answer: B-D
c. monocytes/macrophages and lymphocytes
Which of the following is/are causes of inflammation?
a. infections
b. tissue necrosis (e.g. liquefactive; caseous)
c. foreign bodies
d. immune rxns (hypersensitivity, allergies)
Answer: All
There are 3 major components involved in acute inflammation:
- dilation of small vessels to inc blood flow
- Increased vascular permeability
- Leukocyte emigration
Emigration of the leukocytes (and fluid) from the vascular space (extravasation) to the site of injury occurs where?
Post-capillary venules
*tight junctions simpler in venules than in arterioles
Vasodilation in a component of acute inflammation. It results in increased vascular permeability and is induced by several mediators.
What are these mediators?
- Histamine
- -erythema and heat
- -endothelial cell retraction
–transudate of fluid into interstitial tissue (swelling and edema)
True/False: Stasis of flow during acute inflammation can lead to vascular congestion. This is often due to dilation and permeability as fluid leaves the vascular space
True
- congested blood contains neutrophils which accumulates along the endothelium
- heat and redness
Neutrophil recruitment involves:
- Margination
- Rolling
- Adhesion
- Migration
Margination leads to #’s 2, 3, and 4. It involves ________ release (acute phase reaction) that brings RBC’s closer together, and causes margination of neutrophils out of the central axial column by red cell groups.
Fibrinogen
NOTE: IL-1 and TNF (cytokines) stimulate adhesion molecule expression on endothelial cells and neutrophils
Neutrophil recruitment involves:
- Margination
- Rolling
- Adhesion
- Migration
Loose rolling involves
Selectins
Neutrophil recruitment involves:
- Margination
- Rolling
- Adhesion
- Migration
Adhesion is stable and firm. It involves _______ on neutrophils that are activated by C5a and LTB4
B-2 integrins
*inhibited by corticosteroids and catecholamines
Neutrophil recruitment involves:
- Margination
- Rolling
- Adhesion
- Migration
Neutrophils will migrate out of the vessel into the tissue via ____1____, where it travels between endothelial cells and exits the blood vessel, and via ___2_____ where they travel through the interstitium to the site of injury guided by chemotactic signals
- Diapedesis: b/t endothelial cells out of blood vessel
2. Migration/Transmigration: through interstitium to site of injury
Leukocyte recruitment (chemotaxis) is induced by chemo-attractants (chemotactic agents) that attract the cells to the desired site (e.g. injury, infection, dead tissue).
Chemo-attractants can be endogenous or exogensous. What are examples of endogenous and exogenous chemicals?
- Exogenous
- -bacterial products (peptides)
- -LPS (lipopolysaccharide) - Endogenous
- -cytokines (IL-8)
- -complement (C5a)
- -arachidonic acid metabolites (LTB4)
*which leukocyte involved varies w/ type of response and stimulus
True/False: movement of neutrophils includes extension of filopodia and polymerization of actin
True
A process of getting rid of and degrading the injurious element (or dead tissue).
It involves the following steps:
- recognition and attachment
- engulfment
- killing/degradation
Phagocytosis
- Recognition of foreign antigen or opsonin (C3b) placed on microbe to target it for phagocytosis
Intracellular destruction occurs within the newly created phagolysosome inside the immune cell.
It uses the following to induce destruction:
- ROS
- Reactive Nitrogen species
- Lysosomal enzymes
What are examples of Reactive oxygen species used to induce destruction>
Answer: all of the above
- Superoxide O2-
- Myeloperoxidase (MPO)
- -NADPH oxidase system
- -converts H2O2 to hypochlorite/hypochloric acid (bleach)
* *microbial killing
Intracellular destruction occurs within the newly created phagolysosome inside the immune cell.
It uses the following to induce destruction:
- ROS
- Reactive Nitrogen species
- Lysosomal enzymes
There are two types of lysosomal enzymes: primary and secondary. How do they differ?
- Primary
- -azurophil
- -MPO, lysozyme, defensins, acid hydrolases, neutral proteases
- -NADPH oxidase system - Secondary
- -specific
- -lysozyme, collaginase, gelatinase, lactoferrin, plasminogen activator, alkaline phosphatase, histaminase
Leukocyte adhesion deficiency is characterized by a defect in _______, part of the B-2 integrin family (CD11a; CD18). It results in impaired migration and chemotaxis and recurrent bacterial infections (e.g. gingivitis).
Defect in LFA-1 integrin
- impaired wound healing
- delayed separation of umbilical cord (>30days)
- neutrophils in plasma (not at sites of infection)
_________ is a leukocyte disorder characterized by a defect in the lysosomal trafficking gene (LYST or CHS1). As a result, there is defective fusion of phagosomes and lysosomes, leading to recurrent infections (staph, strep).
Chediak-Higashi syndrome
- partial albinism
- giant granules (in neutrophils and platelets)
The following describes what leukocyte disorder?
- rare
- inherited defects in genes encoding components of phaogycte oxidase (NADPH oxidase)
- impaired generation of ROS
- Absent respiratory burst
Chronic granulomatous disease
- neutrophils can phagocytose, but can’t kill
- increased susceptibility to skin infections
- in first 2 years of life or delayed in 2nd decade
Diagnosis: dihydrorhodamine DHR (flow cytometry) or NBT dye test (old test)
True/False: In the case of chronic granulomatous disease, neutrophils can phagocytose the organism but cannot kill it. The itnracellular survival of ingested bacteria can lead to the development of granulomas in the lymph nodes, skin, lungs, liver, GI and bones
True
- inc. susceptibility to catalase (+) organisms
- skin infections: pyodermas or abscesses
WIth acute inflammation, biologically active mediators are short lived. Also, neutrophils have a short life span (24 hours – apoptosis).
However, termination of acute inflammation also involves inflammatory stop signals which include
- switch to anti-inflammatory leukotrienes
- anti-inflammatory cytokines (TGF-B)
Chemical mediators of inflammation include:
a. Vasoactive amines
b. Lipid products (Prostaglandins
Leukotrienes)
c. Cytokines
d. Complement products (C5a, C3b)
Vasoactive amines act to dilate arterioles and to increase venule permeability. They are released rapidly during times of injury, Ab binding to mast cells (Type I hypersensitivity) and/or in response to complement (anaphylatoxins). What are examples of vasoactive amines?
Histamine
Serotonin
- -stored as preformed molecules
- -mast cells (richest source)
- -basophils and platelets
Chemical mediators of inflammation include:
a. Vasoactive amines
b. Lipid products (Prostaglandins
Leukotrienes)
c. Cytokines
d. Complement products (C5a, C3b)
Arachidonic acid and metabolites include prostaglandins, leukotrienes and lipoxins. Discuss the function and sources of each.
- Prostaglandins
- -mast cells, endothelial cells
- -vascular/systemic effects on inflammation
- -vasodilation (prostacyclin, PGE1)
- -pain (PGE2)
- -fever - Leukotrienes
- -leukocytes, mast cells
- -vascular and SM rxns - Lipoxins
- -suppress inflammation
- -inhibit leukocyte recruitment
COX-1 and COX-2 inhibitors include
NSAIDS (ibuprofen, naproxen) and Aspirin
Corticosteroids reduce reduce transcription of genes encoding for
COX-2, phospholipase A2, IL-1 and TNF
What are examples of Lipoxygenase inhibitors?
–inhibit leukotriene production
–Zeluton,
*manages chronic asthma
Leukotriene receptor antagonist includes Montelukast which plays a role in management of
chronic asthma
Examples of neutraceuticals include:
- Omega-3 polyunsaturated fatty acids
- Turmeric
- Boswellia serrate resin (Frankincense)
What are their functions?
- Omega 3
- -EPA and DHA
- -shift toward anti-inflamm. mediators (better substrate) - Turmeric
- -multiple inflammation pathways - Frankincense
- -inhibits 5-lipooxygenase
These cytokines are involved in acute inflammation and help to promote the adhesion of leukocytes to the endothelium followed by subsequent migration.
TNF and IL-1
*local and systemic effects
(endothelial activation and leukocyte activation)
*fever, sepsis (TNF), cachexia
True/False: TNF-antagonists are standard disease modifying agents (DMARDs) of major chronic autoimmune diseases
True
This cytokine plays a role in acute inflammation and also in cancer. It stimulates the growth of B lymphocytes and plasma cells via secretion of VEGF.
IL-6
*acute phase proteins, C-reactive protein and fibrinogen
Which cytokines trigger acute phase response? Sepsis? Fever?
Acute phase response: IL-1, IL-6
Sepsis: TNF
Fever: IL-1
This system consists of soluble proteins and membrane receptors. It acts as one mechanism of host defense against microbes.
Complement
3 pathways:
- CLassical: fix C1 to Ab
- ALternative: microbial surface molecules
- Lectin: mannose binding lectin binds catbs on microbes – activates C1
**Critical step: Cleave C3 by C3 convertase into C3a and C3b
Effects of the complement system include:
a. inflammation
b. chemotaxis of granulocytes and monocytes (via C5a(
c. activation of lipooxygenase pathway of arachidonic acid metabolism
d. opsonization by C3b and phagocytosis by neutrophils and macrophages
Answer: all of the above
a. Inflammation
–C3a, C5a inc. vasodilation and permeability
(anaphylotoxins)
c. lipooxygenase pathway:
- -generate 5-HETE and leukotrienes
Deficiency of terminal complement components (C5-C9) predisposes to _______ infections
Neisseria
True/False: Bradykinin Increases vascular permeability and dilation, smooth muscle contraction, and pain. It is likely a major component of sunburn injury
True
This type of inflammation usually involves cell-poor fluid and lacks significant numbers of neutrophils and cellular debris.
Examples include:
- Serous effusion: cell poor fluid accumulation in mesothelial lined body cavities
- Skin blister containing few cells
Serous inflammation
Serous effusion: pleura, peritoneum, pericardium
A type of inflammation that is characterized by increased vascular permeability (fibrinogen leakage out of blood). It normally involves inflammation of body cavities, and can occur in settings of hypercoagulability and thrombophilic states
Fibrinous inflammation
Body cavities:
- -meninges
- -pericardium
- -pleura
- scarring if chronic
- *autoimmune disease
ex: Fibrinous pericarditis
Inflammation characterized by pus (neutrophils, liquified cellular debris and edema fluid.)
The abscess is a localized collection of purulent inflammatory tissue.
Purulent inflammation
(abscess)
*seeding of pyogenic bacteria (Staph)
A local defect on surface of organ or tissue due to sloughing of inflamed necrotic tissue. It can only occur on or near a surface (mucosal, skin)
Ulcer
Which of the following is an outcome of acute inflammation?
a. complete resolution
b. healing by CT replacement
c. progression to chronic inflammation
d. all of the above
Answer: all
Is characterized by inflammation, tissue injury, and attempts at repair (coexistence of these). It is not always preceded by acute inflammation
Chronic inflammation
Causes of chronic inflammation include:
- Persistent infections (Mycobacteria, viruses, fungi, parasites)
- Hypersensitivity
- Prolonged exposure to toxic or injurious agents
True/False: Examples of hypersensitivity include autoimmune disease, allergic diseases (asthma) and IBM (idiopathic/multi-factorial)
True
Causes of chronic inflammation include:
- Persistent infections (Mycobacteria, viruses, fungi, parasites)
- Hypersensitivity
- Prolonged exposure to toxic or injurious agents
True/False: Prolonged exposure to injurious agents can include occupational exposure (e.g. silica) and atherosclerosis
True
Morphologic features of chronic inflammation include which of the following?
a. Infiltration with neutrophils
b. Tissue destruction
c. attempts at healing (angiogenesis, fibrosis)
Answer: B and C
Infiltration via mononuclear cells (lymphocytes, monocytes/macros)
What are features of chronic inflammatory bowel disease?
- -relapseing and remitting
- -inflammation/attempts at healing co-exist
- TNF alpha
- elusive (multiple Ags/immune dysregulation)
Macrophages are cells involved in chronic inflammation. They are derived from hematopoeitic stem cells and are a component of the mononuclear phagocytic system.
Which of the following describes their actions?
a. phagocytosis and killing
b. secretion of cytokines and GF’s
c. antigen presentation
d. activate NK cells
Answer: A-C
*activate T lymphocytes
Also: repair, fibrosis, resolve inflammation,
Activation: IFN-gamma
Lymphoytes are extremely important cells in chronic inflammation and in general control/modulation of the immune response.
True/False: Microbes and environmental antigens activate T and B lymphocytes. CD4+ T lymphocytes secrete various cytokines that both promote and direct the inflammatory process, while activated B lymphocytes (and plasma cells) appear in sites of chronic inflammation
True
B lymphocytes/plasma cells:
–form extranodal lymph aggregates
_________ cells are involved in parasitic infections and allergies. They contain Major Basic protein which is toxic to parasites, but can also cause tissue damage.
Eosinophils
_______ cells are distributed in CT. They secrete cytokines and express receptors for Fc portion of IgE.
Immediate degranulation of these cells results in the secretion of Histamine and prostaglandins
Mast Cells
*allergic reactions, anaphylactic shock
(chronic inflammation)
A type of chronic inflammation involving collections of activated macrophages and T lymphocytes (CD4 T cells). Necrosis may be associated with it.
This occurs during an attempt to contain an agent that is difficult to eradicate
Granulomatous inflammation
- macrophages: granuloma
- –varied morphology
- -Epitheliod macrophages/histiocytes
Epitheliod macrophages/histiocytes occur in granulomatous inflammation and are characterized by abundant _______ that resembles epithelium. They can form giant cells, epitheliod giant cells or Langerhans cells.
Cytoplasm that resembles epithelium
There are distinctive types of granulomas:
- FOreign body granuloma
- Immune granuloma
Foreign body granulomas form from inorganic material (suture material, leaked silicone implants). What is the most distinguishing feature?
-lack significant T-lymphocyte mediated response (IFN/interferon)
There are distinctive types of granulomas:
- Foreign body granuloma
- Immune granuloma
Immune granulomas may be induced by
a. persistent T lymphocyte mediated response (IFN/interferon)
b. persistent microbes
c. self antigen
d. suture material
Answer: A-C
**TNF-a (macrophages) maintain granuloma
NOTE: TNF inhibitors can break granuloma down, but can lead to disseminated disease (***Mycobacteria)
________ granuloma is seen most commonly with Mycobacterium tuberculosis. It involves activated macrophages, fibroblasts, T lymphocytes, cellular debris and cellular necrosis (caseous necrosis)
Caseating granuloma
Granulomas w/ giant cells (multi-nucleated macrophages) are most commonly seen in
fungal or other mycobacterial infections
lung
Systemic effects of inflammation: During acute phase response, cytokines (TNF, IL-1, IL-6) are released resulting in fever and the release of acute-phase proteins.
What are these proteins?
C-reactive protein **
Fibrinogen, Serum amyloid A, Hepcidin (anemia)
- regulated by hypothalamus
- mainly IL-6
- proteins secreted by liver
Systemic effects of inflammation: Leukocytosis, or elevated WBC count can occur during acute phase response.
This occurs by:
a. initial release from bone marrow post-mitotic reserve pool
b. eventual increase in production via colony stimulating factors (G-CSF, GM-CSF)
c. protein secretion by lymph nodes
Answer: A, B
- Initial release
- –induced by IL-1, TNF
- -immature (left-shifted neutrophils)
True/False: Left shift refers to a move towards the release of more immature white cell (myeloid) precursors. On CBC, “Left shift” often indicates an infection or other cause of acute inflammation, however can be seen in neoplastic conditions (chronic myeloproliferative disorders, ie-CML
True
Systemic effects of inflammation: Which of the following can be clinical features of the acute phase response?
a. Initial increase in blood pressure and pulse
b. Rigors
c. Chills
d. Septic shock (when severe; TNF and hypotension)
Answer: all of the above
- may only see some clinical features
- Sepsis doesn’t always occur (implies infection)
Leukocytosis can result in increases in different WBC types in blood and tissue.
- ______ increased number of neutrophils (bacterial infections)
- ______ seen in viral infections
- _______ allergies and parasites
- _____ decreased numbers of WBC’s. Associated with certain infections.
- Neutrophilia
- Lymphocytosis
- Eosinophilia
- Leukopenia
Clinical example of severe inflammatory response
Neisseria meningitis
–sepsis
*Tx antibiotics
Regeneration of the previous tissue type (epithelial, skin, mucosal surfaces) and/or deposition of CT is known as
Tissue repair/Healing
__1___ are continuously dividing, while ____2___ tissues are quiescent in the G0 stage of the cell cycle. They have limited potential for regeneration. What are examples of each?
- Labile
- -bone marrow
- -surface epithelium
- -ducts
- -GI
- -urinary - Stable
- -solid organ (liver, kidney, pancreas)
- -endothelial, fibroblasts, SM cells
* *essential in tissue repair
_______ tissues are terminally differentiated. Repair is generally limited to scar formation
Permanent tissues
*neurons, myocardium
Tissue repair involves deposition of CT in “patches” rather than full restoration.
Which of the following accurately depicts the steps in scar tissue formation?
a. Angiogenesis, Granulation Tissue formation, Remodeling of CT
b. Angiogenesis, Lymphocyte invasion, Scar formation
c. Granulation Tissue formation, CT formation, protein degradation
Answer: A
- Angiogenesis
- -bring in O2/nutrients
- -Leaky (edema) - Granulation tissue
- -delicate vessles
- -fibroblasts
- -macrophages and neutrophils - Remodeling of CT
- -scar formation (switch to dense collagen)
- -MMPs
During tissue repair, macrophages and other inflammatory cells secrete cytokines and growth factors that control migration and proliferation of fibroblasts as well as deposition of extracellular matrix proteins. What are the common cytokines involved?
PDGF, FGF-2, EGF
**TGF-B (most important for CT deposition)
*TGF-B inhibited by glucocorticoids
True/False: Vitamin C deficiency impairs collagen synthesis and healing by decreasing the tensile strength of collagen due to abnormal cross linking
True
Cutaneous wound healing via primary intention involves
a. damage to superficial layers
b. repair via epithelial regeneration
c. inflammation, proliferation, materuation
All of the above
-coagulation (fibrin clot)
- Within 24 hrs
- -neutrophils
- epithelial edges migrate/proliferate - By day 3
- -macrophages and granulation tissue - By day 5
- -fibroblast migration
- -collagen and ECM - By week 2
- -edema, leukocytes, inc. vascularity diminish - By end of month
- -scar w/out inflammation
True/False: Cutaneous wound healing via secondary intention involves a combination of regeneration and scarring.
The inflammation is more intesne, there is more granulation tissue present, and a larger scar is formed with wound contraction (myofibroblasts)
True
*seen in extensive tissue loss (ulcers, abscesses, ischemic necrosis)
Secondary cutaneous wound healing involves the formation of a larger fibrin clot, abundant granulation tissue and more necrosis and inflammatory debris. What are the steps to healing?
- Up to 2 wks
- -Type III collagen - After 2 wks
- -Type I
- -remodelling - Wound contraction
- -myofibroblasts
- -close to gap
________, in a pathologic context refers to abnormal or excessive deposition of collagen or other extracellular matrix proteins
Fibrosis
- cause of significant organ dysfunction (cirrhosis, fibrosis)
- myofibroblast, fibroblast recruitment
***TGF-B stimulation
____ involves an injury to the deep dermis. It is most often associated with thermal injury, affecting parallel collagen fibers.
It is generally confined to the borders of the original wound, and has mild amounts of collagen synthesis.
Hypertrophic scar
**tend not to recur w/ resection
______ is due to genetic predisposition. It is due to haphazard (disorganized) collagen arrangement with a hyalinized (glassy and pink appearance). It frequently extends beyond borders of the original wound and a significant amount of collagen is involved.
Keloid
- recurs after resection
- Claw-like projections on gross
______ is when a previously closed wound re-opens due to increased pressure or mechanical stress
Wound dehiscence
________ protrudes above the skin and is referred to as “proud flesh”. It requires cautery or excision
Exuberant granulation tissue
1st messengers interact with
a. kinases
b. phosphatases
c. G proteins
All of the above (intracellular signalling proteins)
Which describes the signal transduction pathway?
a. multiple steps
b. amplification of originnal signal
c. transient activation (on/off)
d. activation of multiple pathways and regulation of multiple cell functions
e. antagonism by contitutive/regulated feedback mechanisms
Answer: all of the above
True/False: There are different types of receptors for 1st messengers:
- cell surface receptors (bind water soluble/hydrophilic first messengers)
- Intracellular receptors (hydrophobic 1sr messengers)
True
*high affinity, high specificity
Cell to cell communication occurs over short and long distances. Response depends on
a. ability of signal to reach target cell
b. expression of appropriate receptor
c. cytoplasmic signalling molecules
All of the above
Permeability of gap junctions is regulated by
a. cytosolic Ca2+
b. H+
c. cAMP
d. membrane potential
e. cytosolic Na2+
Answer: A-D
Steps in the signal transduction pathway are normally reversible (otherwise cancer). Binding of the first messenger to its receptor normally leads to activation of the receptor and production of large amounts of 2nd messengers/downstream signalling proteins such as
cAMP, cGMP, IP3, diacylglycerol, Ca2+,
adenylyl cyclase (amplifer and transducer protein)
Different responses can occur in different cells stimulated with same first messenger. Explain this using the effects of acetylcholine on
a. heart muscle cells
b. SK muscle cells
c. salivary gland cells
a. Heart muscle
- -Ach – Muscarinic
- -dec. heart rate and contraction
b. SK muscle
- -Ach – Nicotinic
- -contraction
c. Saliva
- -Ach – Muscarinic
- -secretion
* lack of = dry mouth
Nitric oxide is used as a first messenger by nerves, macrophages and neutrophils.
What is the process of NO activation and signalling?
- Ach binds endothelial cell receptor
- -wall of b.v. - NO synthase activated
- NO formation (from arginine)
- rapid diffusion of NO across membrane
(acts locally) - NO binds guanylyl cyclase on SM cell
- -GTP to GMP - Rapid SM relaxation and vasodilation
True/False: Mitochondria contain an enzyme that can convert nitroglycerine to NO enabling the relaxation of b.v.’s and decreasing the workload on the heart
True
List the different receptor types involved in cell signaling
- Ligand gated ion channels
–NT’s = direct/rapid signalling
–change membrane potential
(Nicotinic) - G-protein coupled recptors
- -regulate activity of other proteins (enzymes, ion channels)
- -heterotrimeric G-protein – target protein (on/off) - Enzyme linked receptors
- -signal molecule = dimer
- -enzymes/associated w/ enzyme
- -protein kinases – target protein (on/off)
True/False: Steroid hormones regulated early and late gene expression via the early primary response proteins at the nuclear membrane and via regulation of the secondary response genes in the nucleus
True
True/False: Ligand-gated ion channels are ionotropic channels that alter membrane permeability to specific ions. These channels transiently open in response to ligand (NT) binding, and have varying specificty for ions.
True
*ATP, glutamate, glycine, Ach, 5HT, GABA
List the monomeric G proteins
- ras – cell division, proliferation, death
- rho – actin, cell cycle, gene expression
- rab – vesicular transport
- ran – nucleocytoplasmic transport
- arf – vesicular transport
G-protein coupled receptors are serpentine (metabotropic receptors) that make up the largest family of cell surface receptors.
They are coupled to heterotrimeric G-proteins. There are 3 major families of Trimeric G-proteins (I, II, III). List the important family members
I. Gs – alpha subunit
- -adenylyl cyclase
- -Ca2+ channels
I. Golf – alpha subunit
—adenylyl cyclase (olfactory neurons)
II. Gi – alpha, By
- -alpha inhibits adenylyl cyclase
- By activates K+ channels (hyperpolarization)
II. Gt (transducin) –alpha
–cyclic GMP PDE in vertebrate rod photoreceptors
III. Gq – alpha
–phospholipase C-beta
List the steps in GPCR activation
- ligand binds GPCR
- -G-protein associates w/ receptor - GDP released from alpha subunit
- By dissociates from alpha subunit
- -both subunits now active
- -alpha binds GTP
- -By regulates alpha
1 GPCR activates 100 G proteins (signal amplification)
*Note – same ligand can activate multiple receptors
True/False: Signalling through Gas activates adenylyl cyclase and cAMP.
The activated adenylyl cyclase converts ATP to cAMP which activates PKA. PKA then translocates to the nucleus to induce gene expression
True
*PKA: 2 regulatory subunits – catalytic and regulatory
cAMP inhibits regulatory; activates catalytic
Cholera toxin is secreted
by the bacteria Vibrio cholera. It causes persistent activation of adenylyl cyclase via ADP ribosylation of the alpha-s subunit.
Ribosylation of the alpha-s subunit results in
- inability to hydrolyze GTP to GDP
- continuous stimulation of adenylyl cyclase (inc. cAMP and PKA)
**Inc. CFTR-mediated Cl-secretion = secretory diarhea and fluid loss
Activation of Gai inhibits adenylyl cyclase.
What is the result?
hyperpolarization and inhibition of neural activity
Examples: Neuropeptide Y, Ach (M) slows heart rate; a2 adrenergic
Pertussis toxin causes ADP ribosylation of the alpha subunit of Gi. As a result, the alpha subunit remains bound to GDP (inactive) and thus, Gi cannot interact with its receptors.
What is the ultimate result?
Persistent activation of adenylyl cylase and Increased cAMP
*whooping cough
Gq activates phospholipase C - beta which opens
Ca2+ stores/release channels
- cleavage of PIP2 into DAG and IP3
- a1 adrenergic receptor
Intracellular Ca2+ is actively regulated by what mechanisms?
a. Ca2+ pump in ER membrane
b. Ca2+ binding molecules in the cytoplasmi
c. active Ca2+ import into the mitochondria
d. Na2+ drieven Ca2+ exchanger
Answer: all of the above
Each olfactory sensory neuron only expresses one of 1000 Golf receptors and thus responds to a single odorant.
True/False: Gaolf action is similar to Gs in that it stimulates adenylyl cyclase, and increases Na2+/Ca2+ movement (membrane depolarization)
True
True/False: Activation of G alpha T stimulates cGMP phosphodiesterase.
GaT is functionally inhibitory. In the presence of light, GaT activates cGMP PDE which closes Na2+ channels and hyperpolarizes the cell membrane, decreasing NT release.
True
- decreases cGMP
- 1 light activated rhodopsin activates 800 GaT
- retinal rods/cones
Tyrosine kinases are activated by growth factors and insulin.
They dimerize upon ligand binding leading to transphosphorylation (transfer of terminal phosphate onto tyrosine) of tyrosine residues. These phosphotyrosine residues can then act as binding sites to recruit the next players in the cascade by binding proteins containing
SH2 domains
- activates additional kinases and causes phosphorylation
- termination via dephosphorylation or internalization
True/False: Signalling through PI3K promotes cell survival by changing the localization of proteins
True
*phosphorylated lipids (PIP3)
True/False: For receptor serine/threonine kinases, ligand binding causes receptor dimerization and transphosphorylation on S/T residues. This results in the recruitment and phosphorylation of other proteins in the signal transduction pathway
True
Cytokine receptors function in hematopoeisis, immunity, and inflammatory responses. The ligands are typically IL’s and IFN’s.
Which of the following correctly describes cytokine receptor signalling through the JAK/STAT pathway?
a. Cytokine binds
b. Binding results in the recruitment and cross phosphorylation of JAK, a cytoplasmic tyrosine kinase.
c. Activated JAK recruits and phosphorylates other proteins in the signal transduction pathway.
All of the above
There are 3 mechanisms for termination of signal transduction pathways:
- Decrease ligand availability
- Internalize receptor-ligand complex
- Inactivate/desensitize receptors to decrease sensitivity to ligand
Explain methods of decreasing ligand availability
re-uptake, diffusion, enzymatic degradation
There are 3 mechanisms for termination of signal transduction pathways:
- Decrease ligand availability
- Internalize receptor-ligand complex
- Inactivate/desensitize receptors to decrease sensitivity to ligand
What are methods for inactivating/desensitizing receptors?
- conformational change of receptor
- phosphorylation or dephosphorylation of receptor or target protein
- binding of inhibitory proteins that block signalling pathway
There are 3 mechanisms for termination of signal transduction pathways:
- Decrease ligand availability
- Internalize receptor-ligand complex
- Inactivate/desensitize receptors to decrease sensitivity to ligand
Which of the following is a method for internalizing the receptor/ligand?
a. recycling of receptor to the cell surface
b. lysosomal degradation of receptor (decreasing number of available receptors/downregulate)
c. phosphorylation of receptor
Answer A and B
