APPP: Final Review Flashcards
What are the 4 different currents of the AP in the SA node? (4)
- pacemaker current: If – Na+ influx/depolarization
- transient calcium current: ICa(T) – open for short time
- depolarizing current: ICa(L) – slow Ca2+ influx
- repolarizing current: IK – K+ efflux
How is heart function regulated?
when stimulated, ATP is converted to cAMP (which increases PKA)
- cAMP helps open Ca2+ channels, and Ca2+ enters cell and then SR
- cAMP also activates HCN channel in SA node, and Na+ current increases (higher heart rate)
- PKA increases rate of Ca2+ uptake into SR, which enhances relaxation
What pumps are involved in heart contraction? (2)
- Na+/Ca2+ exchanger
- Na+/K+ ATPase
How does pain transduction occur?
- nociceptors detect noxious stimuli from somatic and visceral tissues
- painful stimuli is converted to energy (neuronal AP)
- stimulus sends an impulse across peripheral nerve fibres
Transduction: Nociceptor Activation
Globulin and Protein Kinases
- released by damaged tissues
- ie. kallikrein cleaves kininogen to release bradykinin
Transduction: Nociceptor Activation
Arachidonic Acid
- released by damaged tissues
- metabolized into prostaglandin and cytokines
- prostaglandin blocks K+ outflow from nociceptors via G-protein and PKA cascade, increasing their sensitivity
Transduction: Nociceptor Activation
Histamine
- released by mast cells when tissue is damaged
Transduction: Nociceptor Activation
Nerve Growth Factor (NGF)
- released during inflammation or tissue damage
- binds to TrkA receptors on nociceptors
Transduction: Nociceptor Activation
Substance P (SP) and Calcitonin Gene-related Peptide (CGRP)
- released due to injury
- causes vessel dilation, which spreads swelling around the injury
Transduction: Nociceptor Activation
Other Substances released during tissue damage
- serotonin
- acetylcholine
- low pH solutions
- ATP
What are the 3 principle opioid receptors?
(all members of GPCR family)
- μ (mu)
- Κ (kappa)
- 𝛿 (delta)
What is the result of opioid receptor activation? (3)
- reduced cAMP (and PKA): coupled to inhibitory Gi protein
- reduced neuronal cell excitation and transmission: Ca2+ channels close, neurotransmitter release stops, and K+ efflux
- euphoria: dopaminergic pathways
What are the 2 pathways underlying properties of opiates?
- MOR (mu opioid receptor) agonists reduce excitability and transmitter release
- opiates induce inhibition in VTA on GABAergic interneurons OR reduce GABA-mediated inhibition in NAc and increase outflow from VP – positive reinforcing state
What mediates NSAID inflammatory activity?
inhibition of prostaglandin biosynthesis
Describe how pain is modulated in the body?
- excitatory neurotransmitter (ie. glutamate, substance P, CGRP) mediates synaptic transmission in dorsal horn
- inhibitory neurotransmitter (ie. GABA, glycine, enkephalin, dynorphin, noradrenaline) hinder pain transmission
What factors does successful hemostasis depend on? (3)
- vessel wall
- circulating platelets
- plasma-coagulation protein
Compare how arterial thrombi vs. venous thrombi result.
- arterial: adherence of platelets to arterial wall
- venous: activation of clotting/coagulation system (therefore made of RBC and fibrin), develop in areas of stagnated blood flow
Compare the characteristics of arterial thrombi vs. venous thrombi.
- arterial: pale, granular, lower cell count
- venous: soft, gelatinous, deep red, higher cell count
Compare the management strategy for arterial thrombosis vs. venous thrombosis.
- arterial: anti-platelet strategies
- venous: anti-coagulation strategies
What does clot formation in arterial thrombosis require?
- platelet adhesion, activation, and aggregation
- formation of thrombin, which catalyzes the production of fibrin to stabilize the clot
Arterial Thrombosis
Why don’t platelets normally adhere to healthy arterial walls (endothelium)?
have coated glycoproteins that carry negative charges, which repels against negative charge of endothelial cell coated glycoproteins
Why can platelets adhere to arterial walls upon injury?
injury exposes collagen and other tissue (sub-endothelium), which has positive charges that attract platelets
What receptors are involved in direct platelet adhesion to collagen?
- GPVI – main glycoprotein receptor
- α2β1-integrin
- GPIa
What receptors are involved in indirect platelet adhesion to collagen?
- GPIb – binding via von Willebrand factor (vWF) glycoprotein that is released from injured endothelial cells and platelets
How does platelet activation occur?
- after platelet adhesion, Ca2+ from intracellular stores are mobilized into the cytoplasm
- Ca2+ promotes platelet shape change, and contractile proteins in platelets allow for movement of granules and release of second-wave agonists (TXA2 and ADP)
- TXA2 and ADP enhance platelet activation by binding to their receptors (P2Y12 and TP) to increase intracellular Ca2+, OR activate TXA2 and ADP receptors on other secondary platelets to increase intracellular Ca2+
- increase in Ca2+ stimulates cyclooxygenase to promote synthesis of thromboxane A2
How is thromboxane A2 synthesized?
- Ca2+ activates phospholipase A2, which cleaves platelet membrane phospholipids and liberates arachidonic acid
- in the presence of cyclooxygenase, arachidonic acid forms prostaglandin H2 (PGH2)
- thromboxane synthase facilitates PGH2 metabolism to produce TXA2
What promotes platelet aggregation?
second-wave chemical mediators
- expose platelet surface receptors that are normally inactive on resting platelets, but undergo conformational transformation when there is an increase in Ca2+
What is the predominant receptor for platelet aggregation and how does it act?
GPIIb/GPIIIa
- facilitates contact with circulating proteins – mainly fibrogen, but also vWF
- then fibrinogen can act as a bridge between two platelets with its 2 amino acid RGD recognition sequences
What is critical for platelet aggregation?
interaction between fibrinogen and GPIIb/GPIIIa
- these linkages rapidly enlarge the (primary) platelet plug
What is primary hemostasis?
platelet plug formation at site of injury that occurs within seconds and is key to stopping blood loss
What is secondary hemostasis?
local activation of plasma coagulation factors (ie. thrombin) forms a fibrin clot that strengthens the primary plug
What does each stage of the coagulation cascade involve?
conversion of precursor protein (synthesized in liver) to active protease by cleavage
- non-enzymatic protein co-factor (reaction accelerator)
- Ca2+
- organizing surface (ie. phospholipid surface of activated platelets in vivo)
What are the coagulation proteases of the coagulation cascade?
- HMWK (high molecular weight kallikrein)
- prekallikrein
- factors XII, XI, IX, X, VII, and II (prothrombin)
What are the non-enzymatic protein co-factors of the coagulation cascade?
- factors V, VIII
- tissue factor (TF or thromboplastin) – glycoprotein receptor found on the surface of a number of cells surrounding blood vessels, present on extravascular tissue
How is the intrinsic system of coagulation initiated?
- clotting factors are present inside blood vessels
- activation of factor XII on contact with a negatively charged surface or prolonged exposure to negative charges on endothelial cells
How is the extrinsic system of coagulation initiated?
- initial stimulus (tissue factor) is present outside blood vessels
- damage to blood vessels exposes TF-containing cells from underlying layers to the bloodstream
- with Ca2+ present, TF (receptor) can then bind to factor VII (in blood)
- this sets off sequential protease activations
Where is tissue factor (TF) expressed?
- proposed to be a cell surface, membrane-bound glycoprotein
- leukocytes (under pathological conditions)
- activated endothelial cells (under pathological conditions)
- microvesicles (MVs)
What happens when the intrinsic and extrinsic pathways converge into a final common pathway?
generates thrombin, fibrinogen, and formation of insoluble fibrin
What happens when thrombin binds to thrombomodulin on endothelial cell surfaces?
- prevents it from cleaving fibrinogen
- instead cleaves and activates protein C (in the presence of protein co-factor Va), which inhibits clotting by cleaving and inactivating factor Va and VIIIa (pro-coagulant factors)
What is protein C and what is its function?
- natural plasma protein
- with co-factor protein S (which results in activated protein C), it degrades factors Va and VIIIa – provides natural anticoagulation by inhibiting activation of factor X and prothrombin
How do valves in veins affect venous thrombosis?
turbulent flow and reduced oxygenation of the valve endothelium, which may activate endothelium and allow thrombus to form
- valve pocket sinus can lead to surface expression of adhesion proteins due to its tendency to become hypoxic
What is P-selectin glycoprotein ligand-1 (PSGL-1)?
- expressed by leukocytes
- secretes microvesicles that express PSGL-1 and tissue factor
Venous Thrombosis
- leukocytes and microvesicles binds to activated endothelium via PSGL-1
- leukocytes become activated and express tissue factor
- TF binds to factor VII (and activate it to VIIa) to form TF-FVIIa complex, which activates factor X to Xa
- this initiates coagulation, where lots of thrombin is generated
- local activation of the coagulation cascade overwhelms the protective anticoagulant pathways and triggers thrombosis
What are the functions of the pharynx? (3)
- passageway for food and air
- resonating chamber for sound/voice production
- houses tonsils for immune response
What structures does the larynx contain? (2)
- epiglottis – prevents food/liquid from travelling into trachea and airways
- vocal cords – creates sound
What are the 2 structural changes that occur during branching of the bronchial tree?
- mucous membrane goes from ciliated to non-ciliated
- incomplete C rings of cartilage become plates of cartilage, then no cartilage (smooth muscle instead)
What is Boyle’s Law?
volume of a gas varies inversely with its pressure
What is minute ventilation?
respiratory rate x tidal volume
What is inspiratory capacity (IC)?
tidal volume (TV) + inspiratory reserve volume (IRV)
What is functional residual capacity (FRC)?
residual volume (RV) + expiratory reserve volume (ERV)
What is vital capacity (VC)?
inspiratory reserve volume (IRV) + tidal volume (TV) + expiratory reserve volume (ERV)
What is total lung capacity (TLC)?
vital capacity (VC) + residual volume (RV)
What is Dalton’s Law?
each gas in a mixture of gases exerts its own pressure as if all other gases were not present (partial pressure)
What is Henry’s Law?
quantity of a gas that will dissolve in a liquid is proportional to the partial pressure of the gas and its solubility
What does the binding of O2 to Hb depend on? (5)
- partial pressure of O2: lower PO2 → less O2 combined with Hb
- acidity/pH: low pH → less O2 combined with Hb
- partial pressure of CO2: higher PCO2 → low pH → less O2 combined with Hb
- temperature: higher temperature → less O2 combined with Hb
- 2,3-biphosphoglycerate (BPG): higher BPG → less O2 combined with Hb
What is the chloride shift?
(transport of CO2)
- blood picks up CO2 and HCO3- accumulates in RBCs, creating a high to low concentration gradient
- HCO3- moves out of blood plasma and Cl- moves into RBCs
What is asthma?
chronic inflammatory disease of the airway
What is chronic obstructive pulmonary disease (COPD)?
progressive lung disease
- emphysema and chronic bronchitis are the most common conditions
What is cystic fibrosis?
inherited disorder that affects cells that produce mucus, sweat, and digestive fluids
- leads to severe damage to lungs, digestive system, and other organs
What is acute inflammation and what does it cause?
tissue injury caused by physical or chemical agent or pathogenic microorganism
- capillary widening → increased blood flow
- increased capillary permeability → release of fluid
- attraction of WBCs → migration of WBCs to injury
- systemic response → fever and proliferation of WBCs
- all result in heat, redness, tenderness, swelling, and pain
What are the stages of acute inflammation?
- recognition of danger
- vasodilation and increase vascular permeability
- chemotaxis
- systemic response
Stages of Acute Inflammation
- Recognition of Danger
- tissue resident immune cells (mast cells of macrophages) recognize damage signals through PRRs (such as toll-like receptors)
- recognize pathogen factors (PAMPs) and cells in stress (DNA, heat shock proteins)
- mast cells release stored histamine and NO
- platelets release serotonin
- inflammatory response is initiated
Stages of Acute Inflammation
2a. Vasodilation
- dilation of blood vessels from arteriole → capillary → venule
- stasis occurs when enlarged vessels pack with cells – assists leukocyte migration along vessel endothelium (blood normally flows too fast for directed leukocyte movement)
- increased blood flow to wound sites causes local tissue erythema (redness) and warmth, swelling, painfulness
Stages of Acute Inflammation
2b. Increase Vascular Permeability
- contraction and retraction of endothelial cells allow protein-rich exudate to cross into interstitial tissue
- results in reduced osmotic pressure in blood, and increased osmotic pressure in interstitial space
- leakage of fluid out of blood vessels leads to edema
- when infection is present, edema can spread to nearby lymph channels and lymph nodes (lymphadenopathy)
- increased delivery of immune cells and mediators, and clotting factors
Stages of Acute Inflammation
- Recruitment of Immune Cells – Chemotaxis
What are the WBC migration steps? (3)
- rolling: loose, intermittent contact with endothelium
- adhesion: tight, constant contact with endothelium
- transmigration: WBCs cross endothelial layer through gaps created by contracted endothelial cells
Stages of Acute Inflammation
- Recruitment of Immune Cells – Chemotaxis
Leukocytes are recruited to the site of insult in different phases. What are these 2 phases?
6-24 hours post-injury:
- dominated by neutrophils – first responders, fast arrival
- phagocytes, apoptosis after response
24-48 hours post-injury
- finds monocytes (→ macrophages, APC)
- finds lymphocytes (sometimes eosinophils)
What are the 4 pre-formed acute inflammation mediators released by mast cell degranulation?
- histamine
- cytokines: TNF-a, IL-1, IL-6
- chemokines for neutrophils and eosinophils
- enzymes: tryptase, chymase, cathepsin
Acute Inflammation Mediators
What are the 2 secondary mediators synthesized and secreted upon mast cell activation?
- eiconsanoids: leukotrienes, prostaglandins, and thromboxanes
- Th2 cytokines: Il-4, IL-5, IL-13, GM-CSF
Acute Inflammation Mediators
What do eiconsanoids do?
- increase vascular permeability
- platelet aggregation
- bronchiole constriction
- slower reacting substances, but longer-lasting effects
What are the 6 types of inflammatory exudate and their biological content?
- serous – cell-free plasma (ie. skin blisters, pericarditis)
- fibrinous – with increased fibrinogen for wound repair (ie. adhesions following surgery)
- mucinous – thick clear gel-like mucous provides physical barrier and aid targeting of infectious materials (ie. runny nose with common cold)
- purulent – thick, coloured pus containing WBCs (ie. abscesses, boils, cellulitis)
- sanguineous – fresh bleeding (ie. hematoma)
- mixed types – mixture of the above (ie. serosanguineous, mucopurulent)
Describe the steps of the inflammatory response.
- bacteria and other pathogens enter wound
- platelets form blood release blood-clotting proteins at wound site
- mast cells secrete factors that mediate dilation and constriction of blood vessels – delivery of blood, plasma, and cells to injured area increases
- neutrophils secrete factors that kill and degrade pathogens
- neutrophils and macrophages remove pathogens by phagocytosis
- macrophages secrete cytokines, which attract immune system cells to the site and activate cells involved in tissue repair
- inflammatory response continues until the foreign material is eliminated and the wound is repaired
Mast cells are the source of which mediators of inflammation?
histamine, others
Macrophages are the source of which mediators of inflammation?
cytokines, others
Endothelium is the source of which mediators of inflammation?
NO, cytokines, others
What plasma proteins are sources of mediators of inflammation?
- complement
- clotting factors and kininogens
What are the 4 outcomes of acute inflammation?
- resolution
- abscess formation
- fibrosis (scar) formation
- chronic inflammation
Outcomes of Acute Inflammation
Resolution
- damaging agent removed and damages repair
- organ regeneration and full function restored (normal function)
Outcomes of Acute Inflammation
Abscess Formation
- walled off collection of pus (neutrophils and necrotic tissues)
- may need reabsorption or necrosis
Outcomes of Acute Inflammation
Fibrosis (Scar) Formation
- excessive or abnormal connective tissue (fibrosis)
- hard, non-functional tissue, no organ regeneration (loss of function)
What is septic shock?
- most severe form of sepsis with bacteria/infectious agents in blood
- end organ damage + hypotension
- typically leads to death
What are the 2 types of chronic inflammation mediators?
- macrophages
- lymphocytes
What are the macrophage chronic inflammation mediators? (5)
- proteases
- cytokines: TNF, IL-1 (activates lymphocytes)
- NO
- eicosanoids
- angiogenesis and growth factors: platelet derived growth factor (PDGF)
- fibroblast growth factor (FGF)
What are the lymphocyte chronic inflammation mediators? (2)
- cytokines: interferon 𝛾 (activates
macrophage) - angiogenesis and growth factors: transformation growth factor beta (TGF𝛽), platelet derived growth factor (PDGF), fibroblast growth factor (FGF)
What are granulomas?
accumulations of mononuclear WBCs (macrophage and lymphocytes), epithelioid cells, and multi-nucleated giant cells in injured/damaged tissues
- associated with mycobacterial (TB) or fungal infections
- chronic injury caused by foreign agents such as silica
What are the 5 mediators of tissue repair?
- epidermal growth factor (EGF)
- vascular endothelial growth factor (VEGF)
- platelet derived growth factor (PDGF)
- fibroblast growth factor (FGF)
- transformation growth factor beta (TGF𝛽)
What does epidermal growth factor (EGF) do?
stimulates granulation tissue formation
What does vascular endothelial growth factor (VEGF) do?
stimulates formation of blood vessels
What does platelet derived growth factor (PDGF) do?
promotes growth of fibroblasts and smooth muscle cells
What does fibroblast growth factor (FGF) do?
stimulates formation of blood vessels and wound repair