FDN - Exam 3 Flashcards
What does C4BP do?
C4BP binds to C4b prior to C4b covalently binding to a surface
This inhibts binding and ultimately C3 convertase creation
What causes redness and heat?
Arteriolar dilatation
What enzyme acts on arachidonic acid to make leukotriene A4 (LTA4)?
5-lipoxygenase
What fragment in the complement system accomplishes opsonization?
C3b
What type of necrosis is in this picture?
Caseous (note the granuloma)
Formula for O2 delivery to tissues?
Cardiac output (SV * HR) x O2 content of blood (Hb * Hb sat * 1.34)
Hb sat = [Oxy-Hb]/[Total-Hb] x 100
What is the histological hallmark of cell death?
Disappearance of the nucleus
What is reversible cell injury?
Cell survives due to stress response or adaptation
What receptors on macrophages recognize DAMPs?
Toll-like receptors (TLRs), chemokine receptors, integrins, inflammasome (and various others)
What macrophage cytokine attracts neutrophils to sites of inflammation?
CXCL8
Why opsonization?
For improved recognition of pathogens by phagocytes
What is salicylism?
Dose-dependent phenomena that can cause headache, sweating, tinnitus, and dizziness
Severe forms can cause CNS disturbances, acidbase disturbances, fever, and skin erruptions
What causes leukocytosis in acute inflammation?
Demargination via cortisol and epinephrine (you want to get those WBCs away from endothelium, in the blood stream and to the spot of inflammation)
Stimulation of WBC production via cytokines & CSF (macrophage colony stimulating factors… not CSFluid ;)
“left shift” = release of immature WBCs from the bone marrow via endotoxin stimulation or epinepherine & cortisol
Common findings in SIRS?
hyper or hypothermia
tachycardia
tachypenia or reduced pCO2
leukocytosis or leukopenia (worse option!)
neutrophilia and/or “bandemia”
Possible stimuli for a granuloma?
infection (viral, bacterial, fungal, parasitic), autoimmune disease, cancer, foreign material, unknown (like in sarcoidosis)
Just know that a lot of stuff can cause granulomas!
What are the actions of leukotrienes?
Increased vascular permeability, vasoconstriction, bronchospasm
Acetaminophen is generally well-tolerated for what two reasons?
- It does not cause GI distress
- It does NOT effect platelet function
What activates initiator caspases?
Proteolytic cleavage by pro-apoptotic factors
Do all granulomas involve the adaptive immune system?
No
Does fludrocortisone have glucocorticoid effects, mineralcorticoid effects, or both?
Both.
Low enough doses are given to maintain salt-retaining activity without having anti-inflammatory or antigrowth effects
What is thrombodulin?
A protein expressed on the surface of endothelial cells that serves as a cofactor for thrombin. It reduces blood coagulation by converting thrombin to an anticoagulant enzyme
What are myelin figures?
They are derived from organelle and plasma membranes and represent intracellular whorls of laminated lipid material. Do NOT contain actual myelin.
Most likely represent lipoprotein remnants after cleavage by phospholipases.
What are the effects of Thromboxane A2 (TXA2)
Vasoconstriction, platelet activation (pro-coagulant), and decreased blood loss
What is a lipopolysaccharide (LPS)? What kind of negative effect can it have?
A compound or complex of lipid and carbohydrate
Endotoxin is an LPS released from the cell walls of gram negative bacteria that produces septic shock
What is the inflammasome?
A cytoplasmic multiprotein complex that senses cytoplasmic PAMPs and DAMPs
What agents cause granulomas?
Phagocytized but not eliminated (like inert TB) or viruses present in the cytoplasm
These result in persistent stimulation of the adaptive immune system & epithelioid cells
What percentage of genes are regulated by glucocorticoids?
10-20%
How can inflammation be modified pharmacologically?
Via vasoconstrictors, anti-histamines, receptor blockers, etc
Is diapedesis characterized by strong or weak endothelial-leukocyte interactions? What molecules particpate in binding in this stage?
Strong endothelial-leukocyte interactions
PCAM (CD31) on the endothelium and PECAM on the leukocytes are involved
Both PECAMs are inducd by endotheial and WBC activation
What ROS are generated by macrophages?
superoxide anion -> hydrogen peroxide -> hydroxyl radical + nitric oxide (NO)
What is responsible for the conversion of fibrinogen to firbin?
Thrombin (IIa)
What does the CR3 receptor on phagocytes recognize?
Bacterial CH2O
More info via Google: Complement receptor 3 (CR3)(CD11b/CD18) is a human cell surface receptor found on polymorphonuclear leukocytes (mostly neutrophils), NK cells, and mononuclear phagocytes like macrophages. CR3 is a pattern recognition receptor, capable of recognizing and binding to many molecules found on the surfaces of invading bacteria. CR3 also recognizes iC3b when bound to the surface of foreign cells. Binding to the receptor causes phagocytosis and destruction of the foreign cell.
What disease state is shown here?
ARDS
What does fibrinoid necrosis look like at the macroscopic level?
Nothing. We can only see it at the microscopic level
How and where is nitric oxide (NO) generated?
It’s generated in the cell cytoplasm via iNOS (inducible NO synthase)
Toxicity due to withdrawal of steroid therapy can be caused by what two things?
- Potential flare-up of the underlying disease
- Adrenal glands may have atrophied & it will take weeks to months for HPA axis to return to normal
Do NSAIDs reduce the body temperature in all situations?
No, only when the temperature is elevated
What percentage of O2 from aerobic respiration forms ROS?
1-5% (majority becomes water!)
What is plasma cortisol bound to?
90% bound to Corticosteroid Binding Globulin (CBG), remaining 10% bound to albumin
What are some examples of positive acute phase reactants?
Immune-related (complements, MBL), anti-proteases like alpha-1-antitrypsin & alpha-2-macroglobulin, redox participant ceruloplasmin (+ Fe transport)
What is serous inflammation?
Predominance of fluid (inflammatory edema)
Fluid can come from blood stream (i.e. transudate) or from mesothelial cells lining a cavity
What is systemic inflammatory response syndrome (SIRS)?
Detrimental systemic response to acute inflammation
Mediated by higher circulating concentrations of TNF-alpha (most important), IL-1beta, PAF, etc
What type of acute inflammation is shown here?
Fibrinoid
What are the different types of emboli?
Thromboembolism: embolization from a thrombus (VTE: venous thromboembolism)
Septic embolism: mass of bacteria or fungi (endcarditis)
Fat embolism: following trauma to a bone
Cholesterol: following plaque rupture
Air embolism: nitrogen bubble (rapid assent in diving)
Foreign body: catheter, bullet
Name a COX-2 selective inhibitor. What does it treat?
Celecoxib (brand name: Celebrex)
8-10 fold selective for COX-2, lacks COX-1 side effects
Approved for RA, osteoarthritis, and acute pain
How is acute inflammation resolved?
- Removal of the inciting stimulus via control/elimination of infection or removal of necrotic cells
- Repair of injury via fibroblasts, endothelial cells, epithelium, etc
Where does most ROS come from in the cell?
Oxidative phosphorylation in the mitochondria Some from peroxisomes
In the classical pathway, what makes up the C3 convertase?
C4b2a
What is different about a neutrophil moving toward a chemoattractant?
The leading edge (lamellipodium) lacks organelles
There are a higher number of receptors at the leading edge (these receptors bind to substances that stimulate chemotaxis)
Note that the “tail end” of the moving neutrophil is called the uropodium (just think of what area a urologist works in)
What four molecules trigger P-selectin release from Weibel-Palade bodies? Also include what secretes the molecule.
- Histamine - mast cells
- Thrombin - clotting cascade
- PAF - various cells including endothelium and macrophages
- TNF-alpha - macrophages
Once activated, what odes executioner caspase do?
It degrades the caspase-activated DNase (CAD) inhibitor, iCAD, thus activating CAD. Nuclear DNA is cleaved in 200bp fragments
How do platelets aggregate?
A conformational change in GPIIb/IIIa allows it to bind fibrinogen (GPIIb/IIIa can also bind VWF)
Platelets also released thromboxane A2 (a pro-clot forming prostagandin derivative)
Neutrophils are numerically elevated most often in response to what type of infection?
Bacterial
Are leukotrienes arteriole vasodilators?
Nope
What is karyolysis?
DNA degradation by endonucleases; lysis of nucleus Observed in necrosis ONLY (no apoptosis)
What happens in the three stages of blood clotting? Which two stages occur at the same time?
Primary hemostasis: platelet “plug”
Secondary hemostasis: fibrin formed
Tertiary hemostasis: Fibrin cross-linked
Primary & secondary occur at the same time
What leukotriene product is found in mast cells, macrophages, and basophils?
Leukotrienes C4, D4, and E4
Exposed subendothelium presents what factor that can bind to a certain factor in the blood, intiating secondary hemostasis/blood clotting?
Tissue Factor (TF) from subendothelium binds to Factor VII in the blood
Active form: TF/VIIa
What complement regulators are located in the plasma?
C1INH, C4BP, Factor H, and Factor I
What are the adverse manifestations of SIRS?
Exaggerated or aberrant APR findings (ex: decreased WBC count; very high or very low temp)
Shock
Disseminated intravascular coagulation (DIC)
multi organ failure
If the source of a thromboemboli is an arterial thrombus, what is a possible consequence?
Stroke
What is responsible for the systemic effects of acute inflammation?
Cytokines!!
Endogenous DAMPs, exogenous PAMPs
What is gangrenous necrosis?
Subtype of coagulative necrosis caused by ischemic necrosis of an extremity (with or without concurrent infection), ischemic necrosis of the bowel, or tissue necrosis due to significant infection
How do exudates form?
Via inflammation, direct injury (trauma, infection) or via crush injury (rhabdomylosis)
What causes smooth muscle relaxation of ultimately hyperemia?
NO (nitric oxide) secreted from endothelial cells
What is the normal cellular response to chronic irritation (physical or chemical)?
Metaplasia
What three things can cause an infarction?
- Thrombus
- Embolus
- Mechanical factors (vessel compression, mechanical obstruction)
Are prostaglandins primary mediators of vascular permeability?
NO. They potentiate the actions of other agents
What does LTB4 do?
Attract more leukocytes (aka leukocyte chemotaxis)
If ACTH is lost, will we still have aldosterone production?
Yes, it only decreases by about 50%
What chemical mediators are responsible for arteriolar dilatation? Include the major source as well.
Histamine -mast cells
Serotonin - platelets
Bradykinin - plasma
PAF - various cells, platelets, endothelial
What is Budd-Chiari syndrome?
Hepatic vein thrombosis. Liver swells, increased portal vein pressure
Why is opsonization important?
Necessary for control of infections due to encapsulated bacteria
These capsules impair phagocytosis but opsonized pathogens are more readily phagocytized
What does Factor H do?
It inhibits Factor B binding to C3b in the alternative pathway & stimulates Factor I to degrade C3b
iC3b becomes C3c and C3dg
This is beneficial if/when C3b accidentally binds to self. Factor H determines if C3b goes down the alternative pathway or the degradation pathway
What type of nuclear change is observed here?
Pyknosis
Do we see organelles in blebs in necrosis or apoptosis?
Apoptosis
What type of acute inflammation is shown here?
Serous inflammation
What are examples of clinically significant biomarkers of cell injury?
Troponin from cardiac muscle, transaminase from hepatocytes, and alkaline phosphatase from bile duct epithelial cells
What type of macrophage provides positive evidence of chronic pulmonary congestion?
Hemosiderin-positive macrophages aka “heart failure” cells
How are damaged lipids repaired?
They’re not. They’re degraded by phospholipases (harmful degradation products!)
What causes swelling in typical cases of inflammation?
Venular permeability
How is the classical pathway initiated?
By the production of a C1 Esterase
C1q can bind directly to a pathogen, CRP molecule, or to an antibody. Once bound, C1r aquires enzymatic activity and cleaves C1s to generate a serine protease. C1s then acts on C4 and C2.
Is attachment characterized by strong or weak endothelial-leukocyte interaction? What molecules are involved in binding?
Strong endothelial-leukocyte interaction
Integrins (LFA-1, Mac-1, and VLA-4) on the leukocyte bind to immunoglobulin super(gene) family (ICAM-1 and VCAM-1) on endothelial cells
Can glucocorticoids bind to mineralcorticoid receptors?
Yes.
An enzyme that converts cortiol to cortisone in some tissues stops this effect (cortisone has minimal affinity for aldosterone receptors)
Hyposecretion of the adrenal gland is what?
Hypersecretion of the adrenal gland is what?
Hypo = Addison’s
Hyper = Cushing’s
What complement fragment is responsible for opsonization?
C3b
(the first goal of the C’ cascade is to opsonize target pathogens!)
What acivates I -> Ia pathway?
IIa
What is a corticosteroid? Name the two types.
A hormone produced by the adrenal cortex
Glucocorticoids and mineralcorticoids
How do macrophages trigger inflammation?
Cytokine secretion
Patients taking ______ should not take Aspirin due to bleeding risks.
Warfarin
Unsuccessful repair of inflammation can lead to what?
Abscess, chronic inflammation, and granulomas
What are the three main sources of cellular stress?
Exogenous - physical, exogenous - biological, endogenous
How would you classify Ibuprofen and Naproxen (Aleve)?
Non-selective/non-salicylate drugs
More potent but NOT more efficacious than Aspirin
What is the normal cellular response to decreased nutrients and decreased stimulation?
Atrophy
Inhibiting COX may divert to the lipoxygenase pathway and increase production of leukotrienes. In what disease is this relevant?
Asthma
What is acute respiratory distress syndrome (ARDS)?
A clinical syndrome of severe dyspnea (shortness of breath) of rapid onset, hypoxemia, and diffuse pulmonary infiltrates leading to respiratory failure
What is chemotaxis?
Locomotion along a concentration gradient
How can acute phase proteins be classified? What is the reasoning behind this classification?
Positive and negative
Positive reactants are increased during acute phase inflammation, but this comes at the cost of the production of other proteins (negative reactants)
Can phagocytes recognize the sterile products of injured or necrotic cells to initiate inflammation?
Yes!
They have receptors that recognized DAMPs (damage/danger associate molecular patterns)
What are free radicals?
Molecules containing unpaired electrons They form covalent bonds with other molecules and impair or block function; chain reaction of covalent bonds amplifies molecular damage Arise from endogenous and exogenous sources
What attracts NSAIDs to areas of inflammation?
low pH of inflammatory environment
What is a scab?
A crust formed by the coagulation of blood (fibrin), pus (neutrophils), serum, or a combo
Forms on the surface of ulcers, erosions, or other types of wounds
What reaction creates the hydroxyl radical in macrophages? What element is required for this reaction?
The Fenton rxn
Iron (Fe) is required!
What WBC is VLA-4 (an integrin) present on?
monocytes
What comprises exudate?
Plasma (C’ and Ig) and cells (neutrophils and macrophages)
What are the two pathways that trigger apoptosis? What enzyme do those pathways converge on?
Extrinsic and Intrinsic Caspases
What is the first change in most cell injury? Is this reversible or irreversible?
Cloudy swelling Reversible
What does ionizing radiation do to DNA?
It fragments it/causes double strand breaks
What are some possible results of toxicity due to continued use of supraphysiological doses?
Hyperglycemia, psychosis, osteoporosis, ulcers, edema, hypertension, impaired wound healing, etc
What prostaglandin is indirectly responsible for pain?
PGE2
What are the effects of PGE2, PGF2alpha, PGD2?
Vasodilatation, increased vascular permeability, but NO platelet effects
What is paroxysmal nocturnal hemoglobinuria? What causes this?
A deficiency in GPI (membrane anchors) stops CD55 and CD59 from being attached to cell surfaces. The regulation of the complement system is now irregular (primarily lack of CD59 causes pores to be made in RBCs [CD59 normally inhibits C9 in polymerizing and making the pore!] - Hb leaks out and collects in urine overnight. These people have VERY dark urine in the morning)
What type of necrosis is seen here?
Fibrinoid
Eosinophils typically increase in concentration in the blood in response to what type of infection and what type of immunologic condition?
Parasitic infection and allergy
What are the two categories of glucocorticoid toxicity?
- Toxicity due to withdrawal of steroid therapy
- Toxicity due to continued use of supraphysiological doses
What is metaplasia? Provide an example.
Change in phenotype of differentiated cells, often in response to chronic irritation May result in reduced function or increased propensity for malignant transformation Chronic exposure to cigarette smoke leads to this in the bronchus (pseudostratified to stratified squamous)
What are the signals from injured or necrotic cells that trigger inflammation when perceived by macrophages?
DAMPs - Danger (or damage)-associated molecular patterns
What is autophagy?
Formation of double membrane autophagosome around damaged or unnecessary cell components followed by fusion with lysosome, degradation, and recycling of building blocks to cytosol for new synthesis
What are giant cells?
Arise from macrophage fusion
Nuclear division but not cytokinesis
Do NOT require T cells but can be induced by them
What are the phagocyte receptors for IgG bound to a pathogen and C3b bound to a pathogen?
IgG (bound to pathogen) - FcyR (on phagocyte)
C3b (bound to pathogen) - CR (on phagocyte)
What inhibits Aspirin/what should a patient taking Aspirin not take concurrently?
Ibuprofen
Note: ibuprofen binds reversibly
What are the typical manifestations of APR?
Fever (1-4*C increase)
Acute-phase proteins are altered
Leukocytosis (Increased WBC count)
What triggers platelets to release serotonin, histamine, and produce PAF?
Platelet adhesion followed by platelet aggregation
What cells are involved in healing?
Macrophages, platelets, fibroblasts, endothelial cells, epithelial cells
What molecule is the precursor for leukotrienes and prostaglandins?
Arachidonic acid
What three things does cortisol inhibit?
- CRH
- ACTH
- Inflammatory cytokines (IL-1, IL-2, IL-6, and TNFa)
What are myelin figures?
Dark whorls and aggregates that look like myelin inside cells but are not Caused by damaged and abnormal membranes
What is the mechanism of action of glucocorticoids?
They dimerize with a receptor in the cell cytoplasm and then either act as transcription factors in the nucleus or stimulate other TFs to act
What cardiovascular concerns are there in regards to NSAIDs?
They increase blood pressure (due to sodium retention in the renal tubules & via interactions with catecholamines & angiotensin II)
Do all forms of swelling result from exudates?
Nope. Transudates can cause swelling too
The synthesis of what requires free radicals?
Prostaglandins
What leukotriene product is found in neutrophils and macrophages?
Leukotriene B4 (LTB4)
What fragment in the complement system recruits inflammatory cells?
C5a
What are the clinical findings in a pulmonary embolus?
Shortness of breath, chest pain, tachypnea, and hemoptysis (with infarction)
What protein is a key trigger for apoptosis (hint: from the mitochondria)?
Cytochrome C
Blood clotting involves the interaction of what three “systems” (more like things)?
Blood vessel wall (endothelium), platelets, and plasma protein clotting factors (like VIII)
What are the roles of platelets in acute inflammation?
Hemostasis, wound repair, and secretion of products to cause acute vascular changes (like platelet-derived growth factor) They also release serotonin, histamine, and platelet-activating factor (PAF) to cause vascular effects (dilatation and increased permeability)
What are these cells?
Atypical lymphocytes
We can tell bc they’re larger than normal, have more cytoplasm, and have nucleoli in their nucleus
What type of WBC is elevated most often in response to viral infection?
lymphocyte
Irreversible cell injury can end with either _______ or _________
necrosis (cell lysis) or apoptosis
What is suppurative (or purulent) inflammation?
Pus! Neutrophils (alive or dead), cellular debris, and possibly dead tissue
Usually caused by microbial pathogens
What are the major effects of ATP depletion?
- Impaired Na+/K+ (causes influx of Ca2+, efflux of K+, ER swelling, cellular swelling, loss of microvilli and blebs) 2. Increased anaerobic glycolysis -> lactic acid formation -> decreased pH -> nuclear chromatin clumping 3. Inhibition of protein synthesis -> impaired response to stress and adaptation
What activates X -> Xa pathway?
IXa + VIII
What are the two basic components of acute inflammation?
vascular changes and cellular changes
What are reactive oxygen species (ROS)?
Chemically reactive and unstable forms of oxygen Most ROS are formed as toxic byproducts of cellular metabolism; but have roles in normal biosynthesis ROS are inactivated by many cellular detoxification pathways (ex: SOD)
How does cytochrome C get out of the mitochondria in the intrinsic pathway?
Bcl2 family creates a permeability pore on the outside of the mitochondria
What is the normal cellular response to cumulative sublethal injury over a long life span?
Cellular aging
What is acute inflammation?
A protective reaction of vascularized tissue to injury. Part of the innate immune system
How can thrombi be classified?
- Arterial - platelet rich, white in apperance
- Venous - fewer platelets, many RBCs, red in appearance
What three mechanisms cause chronic inflammation?
- Failure to resolve acute inflammation
- Repeated episodes of acute inflammation (i.e. persistent stimulus)
- de novo (without apparent acute inflammation)
What part of granuloma formation can cause disease?
Fibrosis
What characterizes an abscess?
A type of purulent inflammation
Produces a caivty due to liquefaction necrosis
When do we see myelin figures? Reversible or irreversible cell injury?
Both! Although they are more prominent in irreversible injury
Does apoptosis have ATP depletion?
No
In what instance is apoptosis pathologic?
In some forms of cell injury like DNA damage that triggers apoptosis
What does glutathione peroxidase (GPX) do?
In its reduced form (GSH) it reacts with ROS (H2O2 or *OH) to yield water and the oxidized form (GSSG)
What is it called when alveoli collapse?
Atelectasis
(Note: with atelectasis the lung can be described as “collapsed”)
Define cell injury
Sequence of events following exposure to stress or source of damage (i.e. nutrient deprivation) that affects essential cell components and their functions in a manner that exceeds the limits of the cell’s adaptive responses
Why is bacterial lysis important?
Because for some bacteria opsonization isn’t enough to control the infection (ex: Neisseria bacterias)
What are the consequences of a venous thrombosis?
Venous obstruction which will lead to downstream blockage of venous return
Extension of the thrombus, embolization (most commonly to lung), and infarction (uncommon)
Results in peripheral edema, leg pain, and warmth
What enzyme creates hydrogen peroxide from superoxide anion?
superoxide dismutase (SOD)
What complement regulators are located on the cell surface?
CD59 and CD55
What is an embolus?
A plug composed of detached thrombus, mass of bacteria, or foreign body that is occluding a vessel
What are examples of endogenous cellular stresses?
Cellular metabolism, inflammation, mutagenesis, immunological anomalies
What does Prostaglandin H-2 (PGH-2) become in mast cells?
PGD2
What is the normal sequence of events in inflammation?
- Cellular injury (necrosis, infection, hemorrhage, etc)
- Vascular changes (hyperemia & increased vascular permeability)
- Leukocyte emigration & leukocyte actions
- Healing with return to normal structure or scar
What cells produce leukotrienes?
Neutrophils, mast cells, macrophages, and various other cells
Where do we see E-selections? Is their expression constituitive, pre-formed, or synthesized on the spot?
on the Endothelium
They are synthesized as needed/as triggered by inflammation
What other vaso-active factors can contribute to shock?
histamine, bradykinin, and serotonin
What are the five major targets of cellular injury?
Plasma membrane
Mitochondria
Ribosomes
Cytoskeleton
Nucleus
What are the six steps of phagocytosis?
What does TGF-beta do in healing?
Stimulates collagen secretion by fibroblasts
(Note: autocrine signaling - fibroblasts secrete TGF-beta to create a positive feedback loop and stimulate themselves)
Does rolling contain weak or strong endothelial-leukocyte interactions? What is the interaction/binding between the two cell types?
Weak interaction
Selectin-selectin binding
Sialyl-Lewisx on leukocytes and P-selectin & E-selectins on endothelium
What is fibrinous inflammation?
Exudation of plasma proteins with fibrin deposition
Typically occurs over a surface like the pericardium, pleura, or peritoneum
What is opsonization?
The process of recognizing pathogens by coating them with C’ components, antibodis, or other opsonins (like CRP)
What are the four actions of complements?
- Opsonization
- Recruit inflammatory cells to sites of infection/inflammation
- Pathogen lysis
- Clearance of immune complexes
** for all of these activities C’ must bind to non-self
What are the consequences of a thromboembolism to the pulmonary artery?
V/Q disturbance (ventilation and perfusion disturbance)
Platelets release serotonin, aterio-venous fistula open, acute hypoxia (+/- death)
What is a purulent exudate?
Exudate rich in neutrophils (PUS); often results from bacterial infection
What fragment in the complement system clears immune complexes?
C3b
If the source of a thromboemboli is a venous thrombus, what is a possible consequence?
Pulmonary embolus to the pulmonary artery
What is the source(s) or HOCl?
Neutrophils and monocytes
NOT macrophages
How does WBC adhesion, TF expression, and direct endothelial injury lead to DIC?
Platelet adhesion and aggregation occurs do to exposed subednothelial collagen (primary hemostasis)
Fibrin formation occurs because TF (in subendothelium!) is exposed (secondary hemostasis)
Both of these events lead to thrombus formation & the eventual exhaustion of clotting factors & platelets
Now we end up with thrombus AND bleeding
What level of ATP loss is require to impair essential functions?
90-95%
What macrophage receptors bind PAMPs?
Pattern recognition receptors (PRRs - like TLRs), inflammasome, and various other receptors
Who is at high risk for a PE?
Those who are obese, have metabolic syndrome, are older, pregnancy, use of OCPs, smoke, have a sedentary lifestyle, and post-op patients
What is protectin (CD59)?
Inhibits binding of C9 to the surface/creation of the MAC
On an H&E, what color changes will you see in the cytoplasm of a cell undergoing necrosis?
Decreased basophilia/less blue Increased eosinophilia/more pink (Remember, eosin is acidophilic and stains basic molecules)
What is the major glucocorticoid in humans?
Cortisol
What triggers mast cells to release histamine?
A lot of things! Physical injury (like trauma or heat), C3a or C5a, certain cytokines, etc
What do ROS do to proteins?
They oxidize and create aldehydes. Carbonyl formation is common, which leads to abnormal covalent bond formation They also cause modifications and issues with cross-linking (cysteine sulfhydryls!)
What are the four possible outcomes of acute inflammation?
Healed
- Resolution w/o scar
- Resolution w/ scar
Lack of healing
- Abscess (liquefaction necrosis)
- Chronic inflammaton
Is there cell lysis in caseous necrosis?
No, a granuloma is made
What is coagulative necrosis?
Dead cell and tissue architecture preserved for at least a few days. Dead cells are slowly removed by infiltrating phagocytes and leukocytes Ischemia causes coagulative necrosis of tissues in all organs except the brain
What are epithelioid cells?
The most characteristic cells of granulomas
Arise from macrophages, display an epithelial-like appearance
May be referred to as “epithelioid histiocytes”
What do ROS do to lipids?
Peroxidation. They react with lipids to yield lipid radicals that then react in chain reactions
Damages membranes (fluidity, permeability, etc)
What causes transudate accumulation?
Increased hydrostatic pressure, low oncotic pressure, impaired lymphatic drainage
What does Prostaglandin H-2 (PGH-2) become in the endothelium?
Prostacyclin (PGI2)
What may fat necrosis lead to?
hypocalcemia
How can pathogen killing be classified?
Oxygen dependent and oxygen independent
What are the stages of leukocyte migration from the circulation into the interstitum?
- Margination
- Rolling
- Attachment/adhesion
- Disapedesis (transit between endothelial cells)
What type of granulomas are present in sarcoidosis?
Noncaseating granulomas
NO caseous necrosis
What is a granuloma?
A type of chronic inflammation
Nodular structure with a core (may contain coagulative or caseous necrosis), layer of modified macrophages (epitheliod cells), and an outer layer of lymphocytes and plasma cells
What cells initiate acute inflammation?
Sentinel macrophage and mast cells
What is pyknosis?
Chromatin condensation; increased basophilia
Observed in apoptosis and necrosis
Is VEGF solely responsible for angiogenesis?
No, fibrboblast growth factor (FGF) also participates
Do pathogens have to be opsonized to be recognized by phagocytes?
Nope!
Phagocytes have PRRs (pattern recognition receptors) so they can recognized PAMPs (pathogen-associated molecule patterns)
What patterns of necrosis can be observed?
Coagulative
Gangrenous (subtype of coagulative)
Liquefaction
Caseous
Enzymatic fat
Fibrinoid
What does Prostaglandin H-2 (PGH-2) become in neutrophils and macrophages?
PGE2
What is a blood clot?
A blood coagulum that is either formed outside of blood vessels or intravascularly after death
What medication treats acetaminophen overdose?
Acetylcysteine (brand name: mucomyst)
It works by replenishing glutathione levels
What type of inflammation are macrophages characteristic of?
Late acute inflammation and chronic inflammation
What are the three self molecules that C’ can bind to for indirect pathogen binding?
- Antibodies (1 IgM or 2 IgG)
- CRP
- MBL
What cells are involved in acute inflammation? What about in chronic?
Acute: neutrophils & macrophages (few lymphocytes)
Chronic: macrophages & lymphocytes (few neutrophils)
What enzyme oxidizes arachidonic acid to make Prostaglandin H-2 (PGH2)?
Cyclo-oxygenase
What do NSAIDs do?
Reduce vasodilation, edema, and pain associated with inflammation
Note: this is ACUTE phase inflammation, whereas corticosteroids inhibit all stages of inflammation
What attracts leukocytes to the sites of injury?
Chemoattractants
What does the LPS receptor on phagocytes recognize?
lipids (ex: gram negative bacteria like E. coli)
What activates II -> IIa pathway?
Xa + V
How is C’ activity initiated?
C’ must be bound of “fixed” to a pathogen to initiate activities
What is hydropic degeneration?
A subtype of vacuolar change where excessive fluid/water is present in cellular vacuoles
What is the maximum healing strength of a wound?
Typially 80%
Vacuolated cells in H&E stain may contain what?
Lipid, glycogen or water
Their content cannot be determined without special staining. Usually you rule out glycogen (glycogen storage diseases) and lipids (fatty liver disease) to settle on water
PAMP recognition by a macrophage stimulates cytokine secretion via what second messenger activation?
NFkB (nuclear factor kappa B)
What determines wound strength?
- Amount of collagen
- Time (cross-linking of collagen increases over time)
What process can result when the fibrinous exudate is not cleared within a cavity?
“Organization”
Conversion of coagulated blood, exudate, or dead tissue into fibrous tissue. Fibroblasts and new blood vessels invest the tissue
Adhesions can develop and constriction of the cavity can occur
What are some examples of negative acute phase reactants?
albumin, transferrin, transthyretin, retinol binding protein
What are the two key changes that occur in cell injury?
Membrane damage + ATP depletion
What happens in the tertiary stage of hemostasis?
Fibrin cross linking and fibrinolysis
How do cytotoxic t cells kill? Which pathway(s) do they utilize?
They can use the extrinsic and intrinsic pathways
Intrinsic - Perforins form pores in target cells and then lytic granule enzymes enter and target apoptosis via caspase activity
Extrinsic - Cytokine-induced killing (i.e. TNF-alpha)
What types of modified macrophages can be observed in granulomas?
Epithelioid cells + giant cells (aka multi-nucleated giant cells)
What macrophage cytokine attracts monocytes to sites of inflammation?
CCL2
What is the typical order of changes in cell injury?
Biochemical -> ultrastructural (EM) changes -> LM changes -> morphological changes visible by the eye
What are the four main causes of ATP depletion?
- Hypoxia 2. Reduced supply of nutrients 3. Mitochondrial damage (ROS) 4. Certain toxins (i.e. cyanide)
In tissues, mononuclear cells are either what WBCs?
Lymphocytes or macrophages
What is hypertrophy? Provide an example.
Increased cell size, often in response to a higher workload. Induced by growth factors produced in response to mechanical stress or other stimuli Seen in the uterus during pregnancy or when building muscle (we just add more myofibrils) **Occurs in tissues incapable of cell division
What is this cell?
mast cell
What does acetaminophen do?
Anti-pyretic (reduces fever), analgesic (reduces pain)
But it is NOT an anti-inflammatory
What is a mural thrombosis?
The formation of a thrombus in contact with the endocardial lining of a cardiac chamber or large vessel
What is the harmful degradation product of phospholipid damage/membrane damage?
lysolipids
Where do we see L-selections? Is their expression constituitive, pre-formed, or synthesized on the spot?
On Leukocytes (neutrophils, monocytes, lymphocytes)
Constituitive expression
What is an amniotic fluid embolism (AFE)?
Originally though to be the entry of amniotic fluid, fetal cells or debris into the pulmonary circulation of women who died during labor
AFE causes some type of anaphylaxis with hypotension. “Anaphylactoid syndrome of pregnancy” probably a better name because fetal tissue or amniotic fluid is not universally found in women who present with signs of AFE
What is the goal of acute inflammation?
Recovery and repair
Where are cytoplasmic and nuclear proteins synthesized?
“free” ribosomes not bound to the rER
What is the major mineralcorticoid in humans?
Aldosterone
What type of cell produces PAF?
Theoretically any cell can. Sources we’re familiar with: neutrophils, monocytes/macrophages, endothelial cells, platelets
What is synthethic cortisol bound to in the blood?
Albumin
What are the potential consequences of an arterial thrombi?
Ischemia (inadequate blood flow & thus nutrient delivery and waste removal)
Infarction (sudden insufficiency of blood supply that produces an area of coagulative necrosis)
What is bigger an “a” or “b” complement cleavage product?
B
EXCEPT for C2a, which is bigger than C2b
What is wet gangrene?
Liquefaction necrosis during gangrenous necrosis
What three things can autophagy do?
- Recycle nutrient for stress responses and metabolic adaptation or drive turnover
- Cause loss of function
- Activate pro-apoptotic pathways
Metabolites of arachidonic acid are called what?
Eicosanoids
Most instances of vaculolar change in the heart is due to what?
Ischemia
What is a cytokine?
A generic term for any immune system communication chemical Ex: interleukin (IL), interferon (IFN), tumor necrosis factor (TNF), chemokine (CC or CXC)
When is caseous necrosis most often observed?
In tuberculosis infections of the lung
What are the effects of prostacyclin (PGI2)?
Vasodilatation, platelet inhibition (anti-coagulant), increased vascular permeability, and increased blood flow
What chemical mediators of inflammation are made from amino acids?
histamine and serotonin
What changes occur in the blood vessels as part of inflammation?
Arterioles vasodilate Venules increase their permeability
What are some of the physiological effects of glucocorticoids?
Mediate the stress response, catabolic, anti-inflammatory, immunosuppressive effects, maintenance of normal BP, modulation of perception and emotional functioning
What is an exudate?
protein-rich fluid derived from blood, accumulates outside of vasculature, usually results from inflammation, with inflammation and time it becomes leukocyte rich
How is NO generation stimulated?
By IFN-gamma and bacteria
What causes hyaline membrane disease?
Deficiency of surfactant in premature infants
This manifests clinically as respiratory distress syndrome (RDS)
What histological changes can be observed with reversible cellular injury that can lead to necrosis?
- Cellular swelling and orangelle swelling
- Membrane blebs without organelles
- Clumping of chromatin (nuclear change)
What two chemical mediators of inflammation are pre-formed and stored?
Histamine and serotonin
What is the second goal of the C’ cascade (generation of what powerful anaphylotoxin)?
Generation of C5a
Anaphylotoxin = pro-inflammatory
What are the features of chronic inflammation?
Mononuclear infiltrate (macrophages and lymphocytes)
Increased tissue destruction
Increased fibrosis
Note: granulomas can result as an expressino of chronic inflammation
What cells are at the greatest risk for hyperoxic cytotoxicity?
Those lining airways and alveoli
What chemical mediators are responsible for increased post-capillary venular permeability?
histamine, serotonin, bradykinin, PAF, and leukotrienes
How does fibrin become crosslinked?
Via Factor XIIIa
Note: Thrombin is responsible for XIII -> XIIIa activation
What is caseous necrosis?
Characterized by granulomas (caseating) that form during chronic inflammation with macrophages and their derivatives
Cheese-like (friable) tissue at the macroscopic level
What is delayed-type hypersensitivity (DTH; type IV hypersensitivity)?
T1 helper cells secrete IFN-gamma and activate macrophages. A granuloma forms
Can diapedesis ever occur in capillaries?
Yes, in the lungs
What does the extent of cell injury depend on?
Severity, Type, and Duration (STD)
How does excess oxygen cause cell injury?
Hyperoxia -> increased ROS -> exhaustion of antioxidant defenses -> cell injury and death
How does target cell or bacterial lysis occur in the complement cascade?
Via the creation of MAC (membrane attack complex)
What is the one exogenous mineralcorticoid that can be adminstered to a patient?
Fludrocortisone
What is a thrombus
A coagulum in the cardiovascular system formed during life from blood constituents
What is the most common radiographic finding in sarcoidosis?
Bilateral symmetric hilar lymphadenopathy
May see honeycombing in more advanced (stage 4) disease
How do macrophages and macrophage-related cells detect injury and/of infection?
Via PAMPs and DAMPs
What enzyme converts superoxide anion (O2-) to hydrogen peroxide (H2O2)?
Superoxide dismutase (SOD)
How is PAF formed?
“Remodeling pathway” of membrane phospholipid.
Phospholipase A2 is activated by increased cytosolic calcium to cleave the phospholipid into a fatty acid and another piece that will be made into PAF
What is irreversible cell injury?
Cell does not survive, past point of no return
What type of cell is this?
Basophil
What are examples of exogenous - physical cellular stresses?
Mechanical force, pressure, extreme heat or cold, pH extremes, toxic substances (i.e. carcinogen), UV or ionizing radiation, hypoxia, ischemia-reperfusion
Cell stress and injury can be _______ or ______
Reversible or irreversible
Is inflammation always beneficial?
Nope! Chronic inflammatory and autoimmune disorders are definitely not beneficial
What is a granuloma?
They form during chronic inflammation to contain a pathogen or foreign substance with layers of activated macrophages, macrophage derivatives, and lymphocytes needed for macrophage activation (distinct inflammatory border)
What do neutrophils use to kill?
ROS!
What is the function of selections? How are they induced on endothelial cells?
Bind CH2O
Induced on endothelial cells by inflammation (from macrophage signaling)
What does the scavenger receptor on phagocytes recognize?
Negatively charged ligands (e.g. lipochoic acids of gram positive bacteria)
What two molecules, released from macrophages, stimulate the expression of E-selectins?
TNF-alpha and IL-1beta
What is apoptosis?
Regulated cell death pathway that requires specific genes and proteins
What is this cell?
Eosinophil
Do human mast cells contain serotonin?
No (unclear of the significance of this)
How does the alternative pathway begin?
C3b is spontaneously generated and deposits on the cell surface of a pathogen. Factor B binds and then is cleaved by Factor D to make Ba and Bb
C3bBb is an unstable C3 convertase
What factor does TF/VIIa activate?
IX -> IXa
What laboratory test can be used to rule out PE in low risk patients?
D-dimer (protein present in blood indicative of a thrombus)
What growth factor(s) do platelets secrete?
PDGF - Platelet-derived GF
TGF-beta (transforming GF-beta)
If the endothelium is NOT intact, what action does serotonin have?
vasoconstriction
What three things are characteristic of an activated macrophage vs. an inactive one?
- Maximal intracellular pathogen killing
- Tumoricidal
- NO production
Thrombin, IIa, is responsible for the activation of what factor?
XI -> XIa
(Note that XIa is responsible for the IX -> IXa pathway)
How are damaged proteins repaired?
They’re not. They’re degraded by ubiquitin/proteasome pathway or autophagy
What does catalase in the peroxisome do?
Uses hydrogen peroxide to oxidize substrates during detoxification rxns Also converts hydrogen peroxide to water and O2 to protect cells from H2O2 damage
What is acute respiratory distress syndrome (ARDS)?
Failure of surfactant production in children and adults who are extremely ill
What events initiate injury that may lead to cell death?
Decreased ATP and membrane injury
Do NSAIDs alter sensory perceptions?
No
Three mechanisms that result in vacuolar change?
- Water swelling into organelles 2. Glycogen accumulation (i.e. glycogen storage diseases) 3. Lipid accumulation (i.e. fatty liver disease from alcoholism, T2DM)
What will NSAIDs do to the GI tract?
Gastric distress, gastric bleeding/ulcers, sudden acute hemorrhage
(effects are dose dependent)
What are examples of exogenous - biological stresses?
Virus, toxin (ex: cholera), drugs (side effect, toxicity), nutrition (deficiency, imbalance, excess)
What is the signal from pathogens that triggers inflammation when perceived by a macrophage?
PAMPs - pathogen-associated molecular patterns
What is shock?
Acute state of inadequate tissue perfusion leading to inadequate delivery of oxygen & nutrients to tissues and then inadequate removal of CO2 and waste
(if untreated you die)
What is the normal cellular response to increased demand or stimulation?
Hyperplasia or hypertrophy
How can leukocytes damage normal tissues?
Inadvertant effects like the bystander effect (get frustrated and release NO, ROS & lysosomal constituents)
Clearance of damaged or dead cells and tissues
Anti-self immune response - autoimmunity
Inability to clear pathogen or inciting agent - chronic inflammation
What does C1 esterase do?
Cleaves C4 into C4b and C4a
Cleaves C2 into C2a and C2b
How do macrophages induce a “systemic” inflammatory response?
Secretion of IL-1beta, TNF-alpha, IL-6, and CXCL8 IL-1b, TNFa, and IL-6 cause fever, IL-6 induces acute phase proteins, and all of them together cause increased WBCs
What type of inflammation do neutrophils participate in: sterile or non-sterile?
Both!
What type of activation does rolling require?
Endothelial
What is a transudate?
Protein-poor, acellular fluid accumulation
What do the Bcl2 family proteins do?
Serve as “sensors” of cell health (e.g. growth factors), stress, and damage to regulate release of pro-apoptotic factors and activation of caspases Bcl2 family is regulating balance between survival and apoptosis (some are pro one and pro the other pathway)
What is COX-1? Where is it located?
A constitutive enzyme involved in the metabolism of arachidonic acid. Involved in many “housekeeping” functions.
It’s found in a variety of tissues including the stomach, colon, kidney, vascular smooth muscle, and platelets
What prevents inflammation during apoptosis?
Phagocytosis of apoptotic bodies
What types of abnormal blood flow cause endothelial injury?
Stasis and turbulence
What are the general causes of circulatory failure that can cause shock?
Pump failure -> cardiogenic shock
Inadequate volume -> hypovolemic shock
Vasodilation -> septic shock, neurogenic shock (anesthesia, spinal cord injury), anaphylatic shock (IgE)
What is granulation tissue?
A temporary healing tissue/reparative tissue characterized by:
- Angiogenesis
- Fibroplasia
Tissue is “bumpy”/granular in appearance
What happens in primary hemostasis (the first stage of coagulation)?
Due to high shear stress, platelets need von Willbrand Factor (VWF) to adhere to collagen
GPIb on the platelet adheres to VWF. VWF adheres to collagen.
Now we get a single cell layer of platelets over the damaged area
What cytokines cause leukocytosis?
IL-1beta, IL-6, TNF-alpha, CXCL8
What is acute phase response (APR)?
Beneficial local & systemic response to acute inflammation
Mediated by lower concentrations of TNF-alpha, IL-1beta, and IL-6
What transcription factor enters the macrophage nucleus to stimulate cytokine release?
NFkB = nculear factor kappa B Key 2nd messenger activated by DAMP recognition
Do you expect to have more or less granulation tissue in fibrous scar healing?
More
Anti-inflammatory effects of NSAIDs are primarily due to inhibition of COX-1 or COX-2?
COX-2
What are the five key targets of cellular injury?
Plasma membrane, mitochondrion, ribosomes, cytoskeleton, and nucleus
How does the extrinsic apoptosis pathway get activated?
Death receptors on cell membranes bind specific ligands (TNF alpha and FasL). This triggers the intracellular death domains to bind to adaptors that will activate initiator caspases
FasL binds Fas receptor -> intracellular death domain binds FAAS adaptor protein -> initiator caspase activated
Once activated, what does the inflammasome activate? What are the steps that lead to cytokine release from the cell from there?
Activation of caspase -> cleavage of pre-made “pre-cytokines” to their active forms: IL-1beta and IL-18 -> cytokine release from cell (Note: initial synthesis of the “pre-cytokines” is done via NFkB)
What are the three patterns of nuclear change?
- Pkynosis 2. Karyorrhexis 3. Karyolysis
What does PDGF do in healing?
Stimulates fibroblast chemotaxis and proliferation
What type of acute inflammation is shown here?
Abscess
How are macrophages different from monocytes?
They’re larger, have more lysosomes and mitochondria, and no longer have myeloperoxidase (MPO) activity
What does VEGF do in healing?
Endothelial proliferation - formation of new blood vessels (angiogenesis)
A successful outcome is the restoration of circulation
What is fibrinoid necrosis?
Special type of necrosis observed in blood vessel walls, often arteries Endothelium damage causes the leakage of plasma proteins and then fibrin and immune complex deposition
How are neutrophils activated during the attachment phase?
Macrophages release the cytokine CXCL8. This activates the integrins LFA-1 and Mac-1 on the neutrophil and increases their affinity for ICAM-1
Cyotokines function in which branch of the immune system: innate or adaptive?
They function in both
What comprises MAC?
C5b + C6 + C7 + C8 + C9
Note: this is the 3rd goal of the C’ cascade!
What is required for inflammation to develop?
Injury and response
What can reverse/change an activated macrophage back to an inactive one?
glucocorticoids
Which WBC can replicate: neutrophils or monocytes/macrophages?
Macrophages
What is the role of neutrophils in acute inflammation?
Phagocytosis of microorganisms to achieve “wound” sterility
What type of nuclear change is observed here?
Karyorrhexis
What is the Homan sign?
Pain occuring on dorsiflexion of the foot; indicative of a DVT
What are the five cardinal signs of acute inflammation?
redness, heat, swelling, pain, and loss of function
What is the role of mast cells in acute inflammation?
Production and release of histamine (and leukotrienes) to increase permeability and achieve arteriolar dilatation
What two antioxidants neutralize free radicals?
Vitamins C and E
What happens to cell size in necrosis? Apoptosis?
Enlarged (swelling) in necrosis Reduced (shrinkage) in apoptosis
Examples of ROS?
superoxide anion O2- (most common), peroxide (O2 2-), hydroxyl radical, hydroxyl ion
What enzymes does a lysosome (and ultimately a phagolysosome) use to digest a pathogen?
Acid hydrolases (including elastase), cationic proteins, lysozyme, lactoferrin, and myeloperoxidase (MPO)
If the endothelium is intact, what action does serotonin have?
Causes dilatation
What cells are involved in acute inflammation?
Immune & related cells: neutrophils, macrophages, mast cells, and lymphocytes (T and B cells)
Hemostatic cells: platelets
Reparative cells: fibroblasts, endothelial cells, epithelial cells
What type of cell is this?
Lymphocyte
Note: lymphocyte’s generally have less cytoplasm like in this picture
How does the lectin pathway begin?
Mannose binding lectin (MBL) or Ficolins L-, M-, or H- bind to MASP-1 and MASP-2
This complex acts as a C1 esterase to act on C4 and C2
What are the two phases of caspase function?
Initiation and execution
What do ROS do to DNA?
They oxidize the bases (ex: 8-oxo-guanosine). This alters base pairing (causes puckering) and causes error-prone replication and transcription
Who should not take a COX-2 selective inhibitor?
Patients at risk for cardiovascual disease or events
What is the net effect of glucocorticoids on immune cells?
Decreased pain and tissue destruction
Immunosuppressive & anti-inflammatory
Note: this is pallative and NOT curative. Underlying cause of inflammation still needs to be treated
How does Aspirin (acetylsalicylic acid) work?
Acetylsalicylic acid is a non-selective NSAID. It irreversibly inhibits COX-1 on the platelet. This inhibits the enzyme for the lifetime of the platelet (8 to 11 days). Remember, platelets are not able to synthesize new proteins so they can’t compensate for this inactivation
Selective inhibition of COX-1 due to impct on platelets in portal circulation
Effect achieved at a very low dose
What requires relatively high doses of NSAIDs? Analgesic effects, anti-inflammatory effects, or anti-pyretic effects?
Anti-inflammatory effects
What is a PE that completely obstructs blood flow called?
Acute cor pulmonale (RV failure)
Leads to death
What is surfactant? What cell type produces it?
Produced by the type II pneumocytes to prevent alveoli from collapsing during exhalation (lowers surface tension)
What organs can fail in SIRS?
Heart, lungs, kidney, liver, GI tract, CNS
What is focal regeneration?
Areas in necrotic field with normal tissue structure
Why do macrophages predominate in the later stages of acute inflammation?
There are fewer monocytes in circulation and there is no reserve pool in the bone marrow
How is paroxysmal nocturnal hemoglobinuria treated?
With Eculizumab, a monoconal antibody against C5
It binds C5 in the circulation and reduces C’-mediated hemolysis (aka C5 can’t be made into C5a and C5b and MAC cannot be created on RBCs anymore)
What complement can kallikrein also cleave?
C5 into C5a and C5b
What are the two causes of ARDS?
- Capillary leak from an endothelial injury -> fluid into the interstitium and then the alveoli
- Ischemia leading to damaged type II pneumocytes. Decreased surfactant leads to atelectasis (alveolar collapse) & diffuse alveolar damage (DAD)
What is COX-2? Where is it found?
An enzyme involved in the metabolism of arachidonic acid. It’s involved in inflammatory responses, fever, and algesia
It is expressed in blood vessels, kidney, heart, and brain
What is hereditary angioneurotic edema (HANE)?
A definciency in C1INH
C2 and C4 are low in the plasma, but C3 levels are normal (C4BP is able to regulate the next step)
Swelling occurs because C2b is converted to a C2 kinin
Bradykinin is also produced in excess because of failure of C1INH to inhibit kallikrein
Healing is initially accomplished by the formation of what tissue?
Granulation tissue
What does C5a do?
- Recrut more neutrophils (chemotactic)
- Enhance phagocytosis by binding to macrophages
What enzymes do leukocytes use to break down the basement membrane?
Collagenases, elastaste (i.e. MMPs), and cathepsin G
What do ribosomes on the rough ER synthesize?
Secretory membrane proteins (channels, receptors, hormones, transporters, cytokines)
In the classical pathway, what comprises a C5 convertase?
C4b2a (C3 convertase!) + C3b = C5 convertase
When and where does the oxidative burst occur?
It begins before phagocytosis is complete and then continues in the phagosome interior
When is C’ activated?
When bound to a pathogen
What is a complement?
System of plasma proteins produced by the liver and monocytes.
They’re heat labile, part of the innate immune system, and have several functions including bacterial lysis
What causes endothelial damage in SIRS that can lead to shock?
Bacterial DAMPs sensed by macrophage -> macrophage releases excess TNF-alpha
This increases WBC adhesion (increased selectins and ICAM/VCAM), fibrin generation (tissue factor!), and causes direct damage to tissue
What is liquefaction necrosis? What are the two ways this can occur?
Dead cells are digested and tissue becomes a viscous liquid
Digestion occurs via autolysis (endogenous enzymes) or heterolysis (exogenous enzymes from inflammatory leukocytes)
What type of cell is this?
Monocyte
What does thrombin remove from fibrinogen to make it active fibrin?
Firbinopeptides A and B
What is Virchow’s triad? What is it describing?
Factors that predispose to thrombosis: endothelial injury, abnormal blood flow, and hypercoaguability
When is the alternative pathway engaged?
When C3b binds to a non-self surface
What are other consequences of acute phase responses?
Anorexia, rigors, chills, somnolence, malaise, wasting of muscle
How does PAF contribute to shock?
Causes arterial dilatation and venular leakage. Leads to pooling of blood and fluid loss into the interstitum —> hypovolemia and then shock
What is hyperplasia?
Increased cell number in response to hormones and other growth factors **Occurs in tissues containing stem cells or with cells capable of cellular division
What growth factor(s) do macrophages secrete?
VEGF (vascular endothelial GF)
PDGF (platelet-derived GF)
TGF-beta (transforming GF-beta)
EGF (epidermal GF)
What is atrophy?
Decreased cell and organ size due to decreased nutrient supply or disuse
What are biomarkers of cell injury and necrosis?
Specific cell proteins not normally present in the blood being present
How does SIRS lead to multi-organ failure?
Hypoperfusion from shock
Direct toxic effects from endotoxins and cytokines (TNF-alpha)
Bleeding and thrombosis (DIC)
What does EGF do in healing?
Stimulates epidermal proliferation to cover surfaces
Successful outcome = restoration of sterility, protection, and reduced fluid loss/homeostasis
What makes C3bBb a stable C3 convertase?
Binding of Factor P (properdin)
What is the role of macrophages in acute inflammation?
- Generation of inflammatory & immune responses
- Phagocytosis of microorganisms and detritus
- Wound repair
What type of acute inflammation is shown here?
Ulcer
What is sarcoidosis?
A systemic granulomatous disease of unknown cause
Most commonly effects the lungs, but also effects lymph nodes, liver, eyes, and parotid glands
Where is Aspirin absorbed? How is it distributed?
Absorbed in the stomach
Distributed widely bound to plasma (~80%)
What does the prostaglandin PGE2 do?
Inhibits stomach acid secretion, enhances mucosal blood flow, and promotes intestinal secretion of cytoprotective mucus
What is the enzyme that makes superoxide anions extracellularly and within the phagosome in a neutrophil?
NADPH Oxidase
Where does enzymatic fat necrosis occur most frequently?
In the pancreas
What cytokines change acute-phase proteins?
IL-6
Where do we see P-selections? Is their expression constituitive, pre-formed, or synthesized on the spot?
On the endothelium and Platelets
They are preformed in Weibel-Palade bodies
What macrophage cytokine activates VCAM-1?
CCL2
What characterizes an ulcer?
Loss of epithelium; often associated with acute OR chronic inflammation
How is bradykinin made?
Signal cascade leads to the cleavage of HMWK (high-molecular weight kininogen) into bradykinin
Kallikrein is needed to stimulate this reaction
What is DAF (CD55)?
Decay activating factor that displaces C2a from C4b2a (inactivates C3 convertase)
What are the principle mediators of anaphylaxis?
Histamine, leukotrienes (SRS-A), and PAF
What are the collective actions of PDGF & TGF-beta called?
Fibroplasia
A successful outcome is the provision of mechanical strength
Noe: excessive fibroplasia can be maladapative and lead to things like keloid scars
What chemical mediator of inflammation is made from a lipid?
PAF
How does the endothelium inhibit thrombosis formation?
Via heparan sulfate, PGI2, and NO release
What are some examples of chronic inflammation?
Atherosclerosis, chronic hepatitis, osteroarthritis, thyroiditis
What chemical mediator of inflammation is made from a peptide?
bradykinin
How are the systemic effects of acute inflammation described?
Beneficial: Acute-phase response
Adverse: systemic inflammatory response syndrome (SIRS)
What happens in a partial PE blockage?
V/Q mismatch; hypoxia, (+/- shock and death)
+/- acute cor pulmonale
+/- chronic cor pulmonale (right side heart failure)
Two mechanisms for the generation of C5a?
- Classical complement cascade
- Kallikrein converts C5 into C5a + C5b
Are the effects of glucocorticoids dose-related?
Yes. The effects become amplified the larger the dose
What fragment in the complement system accomplishes pathogen lysis?
MAC (not really a fragment)
What type of T-cells do macrophages present to in the adaptive immune response?
CD4 T cells
What do LTC4, LTD4, and LTE4 do?
Increase vascular permeability, vasoconstriction (late), and bronchospasm (These are all the slow-reacting substance of anaphylaxis: SRS-A)
What is considered “endothelial activation” during attachment?
Increased ICAM-1 expression (stimulated by TNF-alpha and IL-1beta from macrophages)
What enzyme converts H2O2 into HOCl?
Myeloperoxidase (MPO) (HOCl is bleach!)
Name three antioxidant proteins expressed by cells
- superoxide dismutase (SOD)
- Catalase
- Glutathione Peroxidase
How do you reduce withdrawal toxicity?
- Tapering dose after the therapeutic response is achieved
- Alternate day therapy - reduces side effects and allows recovery of ACTH release
- Localized delivery - whenever possible nonsystemic GC therapy should be used to minimize systemic exposure
What is meant by “oxidative burst”?
Increased O2 consumption by phagocytes leads to increased NADPH Oxidase activity and thus the creation of superoxide anions O2-*
These superoxide anions can then participate in other rxns to make more ROS, which will be used to kill pathogens
What does increased cytosolic Ca 2+ cause? Include specific enzymes that cause these issues
Membrane damage (proteases and phospholipases), nuclear damage (endonucleases), and ATP depletion (due to changes in mitochondrial function)
What ROS are generated by neutrophils?
Superoxide anion -> hydrogen peroxide -> hypochlorus acid & nitric oxide (NO)
Are enzymes that inactivate ROS constitutively expressed or produced when needed?
Constitutively
What is fat necrosis?
Necrosis of fat tissue dur to degradation by lipases, typically released from the pancreas during pancreatitis. FFA react with calcium to produce chalky white deposits (saponification or soap formation)
Severe or sustained ATP depletion leads to what kind of cell death? Necrotic or apoptotic?
Necrotic
How is platelet inhibition achieved via NSAIDs?
TxA2 (thromboxane) isn’t produced & the net effect is the inhibition of platelet aggregation
What type of necrosis is usually seen in immune-mediated vasculitis syndromes?
Fibrinoid necrosis
What type of activation does attachment and diapedesis require?
Endothelial AND leukocyte
What is compensatory anti-inflammatory response syndrome (CARS)?
It’s an anti-inflammtory response to limit or balance SIRS
Presently cannot be altered and still unclear if its beneficial or harmful
What does cortisol have a higher affinity for: glucocorticoid receptors or mineralcorticoid receptors?
Equal affinity for both
Conversion to cortisone by 11B-hydroxysteroid dehydrogenase helps lessen the effects of MR binding
What activates executioner caspases?
Proteolytic cleavage by initiator caspases
What integrin present on a monocyte binds to VCAM-1 on the endothelial cell?
VLA-4
How can you distinguish liquefaction necrosis from coagulative necrosis?
Liquefaction necrosis will have a loss of cell borders In coagulative necrosis cell borders persist for at least a few days
What are the possible consequences of an embolism?
Ischemia or infarction
Note: the distribution of the infarction is often wedge-shaped
What cytokines cause fever?
TNF-alpha, Il1-beta, IL-6
What COX-2 derived prostaglandin is responsible for inhibiting platelet aggregation on the endothelium?
PGI2 (prostacyclin)
What does Prostaglandin H-2 (PGH-2) become in macrophages?
PGF2alpha
What causes turbulent blood flow?
Incompetent valves, bifurcation points, and stenotic vessels
What prevents infarction to the lungs when a PE occurs?
Arterial blood supply via the bronchial arteries
What WBC are LFA-1 and Mac-1 (both integrins) present on?
neutrophils and monocytes
What is karyorrhexis?
Fragmentation of the pyknotic nucleus Observed in apoptosis and necrosis This step may or may not occur
What is acetaminophen a poor inhibitor of cyclo-oxygenase?
acetaminophen is a poor inhibitor of COX-1 and COX-2 in the prescence of high peroxides, which there is at inflammatory sites
What does Prostaglandin H-2 (PGH-2) become in platelets?
Thromboxane A2 (TxA2)
What is a thrombus called if it completely obstructs a vessel?
Occlusive
What molecules stimulate chemotaxis of leukocytes to sites of inflammation? Include the source of the molecule.
PAF from endothelial cells, neutrophils, monocytes, macrophages, platelets, etc
LTB4 from neutrophils and macrophages
C5a from plasma
N-formyl-methionyl peptides
CxCL8 and CCL2 from macrophages
How is monocyte extravasation different from neutrophil extravasation?
There is a second immunoglobulin super(gene) family molecuole present: VCAM-1
What is a Boyden chamber?
A device used to study chemotaxis
