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188 Cards in this Set

  • Front
  • Back
what is the normal range for serum glucose?
70 - 110 mg/dL
what is the normal range for BUN?
20 - 40 mg/dL
what is the normal range for serum creatinine?
2-4 mg/dL
what is the normal range for serum calcium?
8-12 mg/dL
what is the normal range for serum sodium?
135-155 mg/dL
what is the normal range for serum potassium?
3.5-5.5 mg/dL
what is the normal range for serum chloride?
100-115 mg/dL
what is the normal range for serum inorganic phosphorus?
3-8 mg/dL
what is the normal mammalian body temperature?
102 °F or less
what is the normal mammalian WBC count?
5,000-15,000 cells/mm^3
what is the normal range of mammalian RBC count?
4-8 million cells/mm^3
what is a normal hematocrit?
30-45%
what is normal plasma specific gravity?
1.008 - 1.012
what are the four aspects of disease?
1. etiology
2. pathogenesis
3. morphological changes
4. functional disturbances
sequence of events in molecules, organelles, cells, tissues in response to an etiologic agent
pathogenesis
In cycstic fibrosis, a defective gene makes faulty proteins which regulate chloride transport. What is the etiology of this disease?
a faulty gene
what is the pathogenesis of cystic fibrosis?
- fibrosis
what are the functional disturbances and morphologic changes of cystic fibrosis
- faulty proteins that regulate chloride transport
- altered chloride and sodium content in secretions
- viscid mucous
- defective mucociliary transport alters pulmonary clearnance and control of pathogens
- repeated inflammations, inflammation
- fibrosis
the function of cells and maintenance of cell structure within narrow "normal" physiologic ranges
homeostasis
what are some examples of tensors to which the body adjusts to maintain homeostasis?
pH, hydration, temperature, ionic load, barometric pressure, background radiation
hypertrophy, hyperplasia, hypoplasia, atrophy, and metaplasia are all examples of what phenomenon?
adaptation
the uncontrolled proliferation of cells within a tissue
neoplasia
name four major pathways of hypoxia/ischemia
1. loss of blood supply (hemorrhage or occlusive thrombus)
2. loss of perfusion (CV failure, shock)
3. loss of O2 carrying capacity (CO, anemia)
4. loss of oxygenation (pulmonary disease)
List seven major causes of cell injury
1. hypoxia
2. physical agents (mechanical force, heat, cold, radiation, etc.)
3. chemical agents (poisons, drugs, excess metabolites)
4. infectious agents
5. immunologic reactions
6. genetic derangements
7. nutritional imbalances (starvation, obesity, nutrient deficiencies)
*** What are the four primary targets of cell injury?
1. cell membrane integrity (controls structure and homeostasis)
2. aerobic respiration (effecient generation of ATP)
3. synthesis of enzymes and structural proteins
4. genetic apparatus integrity
how long after loss of ATP does irreversible injury occur and how does this manifest?
reversible cell swelling becomes irreversible cell swelling after 20-60 minutes
how long after irreversible cell injury does cell death typically occur?
10-12 hours
how long after irreversible cell injury do morphologic changes become recognizable?
10-12 hours
what are the major qualities of a cell that affect its response to injurious stimuli?
1. type of cell
2. state of cell
3. adaptability of cell
(e.g. brain tissue is more sensitive to hypoxia than muscle)
what are the major qualities of a cell affect its vulnerability to injury?
nutritional, hormonal, and metabolic needs.
(example, the effects of a toxic drug metabolite will be more severe in animals with hepatocytes "induced" with more mixed function oxidases)
what are the four primary biochemical/physiological pathways that affect cell injury?
1. oxygen and free radicals
2. increased intracellular Ca
3. loss of ATP
4. loss of membrane permselectivity
how does Ca influx cause a loss of ATP?
opens pores on mitochondria, causing them to lost their activity (lose proton gradient)
by what two major pathways does loss of ATP affect cell membranes?
1. can't make the enzymes to recycle phospholipids
2. lose active ion transport, resulting in water influx
after cell injury, what is the biochemical basis for a loss of membrane permselectivity?
loss of ATP shuts off calcium pumps. Influx of calcium triggers mitochondria to dump their calcium. So much calcium in the cytosol activates calcium dependent phospholipases, which eat away at the cell membrane and internal membrane structures
what four major enzymes are affected by increased cytosolic Ca and what is the effect on the cell?
1. ATPase - decreased ATP
2. phospholipase - decreased phospholipids
3. protease - damage to membrane and cytoskeletal proteins
4. endonuclease - nuclear chromatin damage
what are the two major sites of intracellular Ca storage that can be disrupted by an injurious agent?
1. mitochondria
2. ER
what is the typical time that a cell will be irreversibly injured if hypoxic?
30-40 minutes (depending on cell type)
what microscopic morphological changes are typical of a cell with a reversible injury?
- swelling
- membrane blebbling
- ER and mitochondria swelling
- clumping of nuclear chromatin
- dispersion of ribosomes
- Calcium densities in the mitochondria
- activation of lysosomes to autophagy
under a microscope, what is the most easily recognized indication of cell injury?
changes in the nucleus
what is pyknosis?
dense condensation of nuclear chromatin
what is karyolysis?
a nucleus devoid of chromatin
what is karyorrhexis?
random fragmentation and degradation of nuclear chromatin following pyknosis
what are the two primary critical events associated with irreversible cell injury?
- inability to reverce mitochondrial dysfunction
- profound disturbances in membrane function (Ca dependent phospholipases and decreased phospholipogenesis)
what five major effects of cell injury cause membrane damage?
1. loss of phospholipids (e.g. through Ca dependent phospholipase activation)
2. lipid breakdown products disrupt membrane integrity
3. cytoskeletal damage causes exfolation of membrane
4. loss of intracellular amino acids - many effects
5. lipid peroxidation - act as detergents that basically "poke holes" in the phospholipid bilayer
what is the major injurious stimulus that would damage a kidney due to a renal infarct?
hypoxia
how can restoration of perfusion cause further tissue damage following an acute infarction?
the spread of free radicals and proteolytic enzymes will occur
what are the four "free radicals" and the enzymes that produce them?
1. superoxide, produced in the mitochondria by oxidases such as xanthine oxidase and cytochrome P450
2. hydrogen peroxide (not actually a free radical) - produced by superoxide dismutase or peroxisomal oxidases
3. hydroxyl radical - hydrolysis of water either by radiation or catalysis by transition metals (e.g. Fe)
4. peroxynitrite radical and other nitric oxide byproducts
what are the four major injurious effects of free radicals in cells
1. lipid peroxidation
2. oxidative modification of proteins (e.g. promotes cross-linking of cysteine residues)
3. DNA damage
4. initiation of free radical chain reactions wherein one free radical can cause multiple damaging chemical reactions
what are the two primary ways in which cells render free radicals harmless
1. antioxidants - scavenge the free radicals
2. enzymes inactivate them (e.g. SOD)
the lack of which nutrients can cause white muscle disease?
Selenium
Vitamin E
what is melena?
coagulated, partially digested blood in the stool.
what are the characteristics of fatty change?
- usually occurs in cells (such as liver) that have a role in fat metabolism
- large fatty vacuoles in the cells
- nuclear and cytoplasmic displacement
- yellow, greasy appearance grossly
what are the two basic biochemical processes that lead to the morphologic changes associated with necrosis?
- degradative enzymes from injured cells
- protein denaturation
a process in which lysosomes inside a cell degrade that cell
autolysis
the process of cell degradation from enzymes derived from inflammatory cells
heterolysis
what are the characteristics of coagulative necrosis?
- protein denaturation
- temporary maintenance of the cell outline (like a "ghost" of the former cell)
what are the characteristics of liquefactive necrosis
- dead neutrophils and leukocytes
- dead bacteria
- cell debris
- liquid/amorphous
what general histological features are associated with most types of necrosis
- increased staining (eosinophilia)
- amorphous cytoplasm
- swollen ER and mitochondria (not usually visible)
- distrophic mineralization (especially calcification)
what is usually associated with caseous necrosis
- Mycobacterial infection or something similar
- body builds a collagenous wall to contain the infection
- "cheesy" appearance due to massive destruction from lysosomal enzymes
what is a typical feature of fat necrosis?
- streaks due to saponification of fatty acids and complexation with calcium
comment on the difference in inflammatory response between necrosis and apoptosis
in necrosis, inflammation is stimulated; in apoptosis, inflammation is not stimulated or usually very mild
what are three pathological routes to apoptosis?
- induction by cytotoxic T-cells
- viral infection
- injurious stimuli such as radiation, heat, and some drugs
what are the two apoptotic pathways?
- intrinsic (mitochondrial pathway)
- extrinsic (death receptor induced pathway)
what are the five basic steps of apoptosis?
1. stimulation and activation of an apoptotic pathway
2. production of executioner molecules
3. degradation of nucleus by endonucleases and breakdown of cytoplasm (e.g. by proteolytic enzymes attacking the cytoskeleton)
4. blebbing, budding, and formation of extracellular apoptotic bodies
5. phagocytosis of the apoptotic bodies by macrophages
what is the current theory of genetically, why apoptosis occurs?
the cells always "want" to undergo apoptosis, but the cell is constantly expressing proteins that are inhibiting apoptosis from occurring. When this genetic machinery breaks down, apoptosis is "allowed" to commence.
what are heat shock proteins and what is their function?
- proteins produced by normal cells to help overcome improper protein folding after an injurious stress
- chaperonins: help unfolded proteins fold correctly
- ubquitin: binds to and facilitates the degradation of misfolded/denatured/damaged proteins
list some common pathogens
- viruses and prions
- bacteria
- fungi
- "special" bacteria such as mycoplasms, chlamydias, and rickettsias
- protozoa
- helminths and other parasites
what are the three primary ways that pathogens damage tissues?
1. contact/enter cells and kill directly
2. release toxins
3. induce host inflammatory reponse - kills pathogen AND body cells
in what ways do toxins released by pathogens damage tissues?
- kill (poison) them directly
- release enzymes that degrade the tissues
- release enzymes that damages vasculature
what is distemper?
- an epitheliotrophic virus
- grows in and lyses cells in a variety of tissues
- clinical signs: cough, cutaneous crusts, seizures, fever, dyspnea
- clinical signs attributable to lesions in brain, lung, gut, eye, urinary bladder
how would the urinary bladder present histologically after an acute canine distemper infection?
- obvious signs of cell injury and/or necrosis
- eosinophilic round viral inclusion particles in the cytoplasm
how would the lung present histologically after an acute canine distemper infection?
- destruction of the "honeycomb" structure of the parenchyma
- congestion consistent with acute pneumonia
- massive accumulation of neutrophils and other inflammatory cells and cell debris in the avleoli
what is the life story of a lysosome?
- born in the RER, where they are packed with hydrolytic enzymes
- grow up in the Golgi as primary lysosomes
- exist in the cytoplasm and fuse with phagocytic vacuoles or autophagic vacuoles (secondary lysosomes aka phagolysosome)
- exocytoses or forms pigment granules such as lipofuscin or hemosiderin
- dies as a residual body
what are the major steps of heterophagy?
1. ingestion of material by macrophages and neutrophils via endocytosis or pinocytosis
2. formation of a digestive vacuole (a phagosome)
3. fusion of the phagosome with a lysosome, which digests the phagocytosed material
4. exocytosis of digested material or formation of pigment granules such as lipofuscin
5. remnants exist as a residual body
what is storage disease?
when lysosomes do not work properly by not having enough enzymes or the enzymes are inactivated, stuff builds up in the lysosomes and kills them
the presence of accumulated ganglioside in neurons is indicative of what? Why is this happening?
progressive storage disease. The lysosomes do not have sufficient enzyme activity in the lysozymes to degrade the ganglioside
what is induction and what are its consequences?
an adaptation of cells due to an increased demand for metabolism characteristic of the production of abnormal amounts of metabolic enzymes and SER hypertrophy.

Induction can effect an enhanced capability for the body to metabolize many drugs and chemicals (such as drugs) in addition to the original injurious agent.
what could you potentially find in liver cells of a dog that has been on a regimen of antiepileptic medication?
Induced hepatocytes:
- SER hypertrophy
- resistance to other medications due to induction
what are the components of the cytoskeleton
- microtubules (tubulin)
- thin, actin filaments
- thick, myosin filaments
- intermediate filaments
what are the major effects of alteration/injury to the cytoskeleton?
- defects in cell locomotion
- defective organelle movement
- accumulation of fibrillar material (fibrin)
what are the four basic types of intracellular accumulations?
- normal stuff such as water, glycogen, and fat
- abnormal stuff such as minerals
- infectious organisms
- pigments
***** What are three types of deposition of intracellular accumulations?
- normal stuff produced at an increased rate but removed at a decreased rate (e.g. fatty change)
- normal or abnormal stuff accumulates because it can't be metabolized (e.g. lipofuscin)
- abnormal stuff deposited that can't be removed (e.g. silica)
what are the major sites of intracellular lipid deposition other than adipocytes?
1. LIVER!
2. heart
3. muscle
4. kidney
what is mucopolysaccharidosis?
a storage disease wherin both lipids and carbohydrates accumulate in the cells in abnormal quantites?
what two terms are used to describe the abnormal accumulation of triglycerides in the liver and heart?
- fatty change
- steatosis
what are the steps for steatosis?
1. absorption of free fatty acids or lipogenesis. Note that this is usually kept in check by lipid catabolism.
2. conversion of free fatty acids to triglycerides
3. binding of apoprotein to form lipoproteins
4. fatty change (steatosis) of parenchymal cells in the body
what are causes of liver steatosis? What are observed morpholgical changes?
causes:
- excess lipid intake
- defective hepatic lipid metabolism (sometimes caused by anoxia)
- alcohol or other liver toxins
- protein starvation

morpholoical changes:
- liposomes
- large liposomes will displace the nucleus and cellular contents to the periphery of the cell
- ruptured cells can cause liposomes to coalesce, forming fatty cysts
- grossly, the liver can appear yellow, heavy, soft, and greasy
what are some pathologic accumulations of intracellular lipid?
- atherosclerosis
- xanthomas (an irregular, yellow, fatty patch, usually on the skin)
- foamy macrophages
- myelin figures
what is the histological feature indicative of intracellular protein accumulation?
hyalin droplets (very eosinophilic)
what histological feature of the kidney would accompany proteinuria?
hyalin droplets in the renal tubular epithelium
how are diabetes mellitus and glycogen related?
glycogen granules will accumulate in the liver, heart, and kidney parenchyma
*** how are intracellular pigments accumulated?
- carbon from air
- tattoos
- *** carcinogens in cigarette smoke

these inclusions are often found in lymph nodes and macrophages
what types of cell injury are apparent by lipofuscin accumulation and how does it present grossly?
- free radical lipid peroxidation
- excessive accumulation of lipids in cachexia (general physical wasting) caused by malnutrition or cancer

may appear as "brown atrophy" of organs
what are some endogenous intracellular pigments?
- lipofuscin (breakdown of lipids)
- melanin
- hemosiderin (a storage form of iron)
- bilirubin (a hemoglobin breakdown product)
under what circumstances would you typically see hemosiderin deposits in a tissue?
- excessive iron from bruising (RBC lysis and phagocytosis)
- transfusions
- hemolysis
- dietary iron overload
- impaired utilization of iron
under which pathologic conditions would you typically see bilirubin and how does it present?
- decreased bile conjugation and excretion from cirrhosis of the liver
- increased loading of bilirubin (e.g. from hemolysis)

- typically accumulates in the liver and kidneys: the major excretory sites of bilirubin
- presents as a green-brown to black pigment
what is the major physiologic difference between dystrophic calcification and metastatic calcification
in dystrophic calcification, there are normal serum Ca levels, whereas in metastatic calcification, there are high Ca serum levels
where does dystophic calcification occur, how does it happen, and what affect does it have on the body?
- found in necrotic tissue with an acidic microenvironment
- formed in two steps: (1) initiation by formation of extracellular vesicles containing calcium and phospholipid (and damaged mitochondria); (2) propagation of the calcium phosphate precipitate

- it can cause organ dysfunction such as cystic and renal calculi and deposition into myocardium
what is metastatic calcification and what can cause it?
- calcification of healthy soft tissues in the presence of hypercalcemia

- can be caused by renal failure, hyperparathyroidism, Vitamin D intoxication, Addison's disease (hypoadrenocorticism), bone tumors, leukemia/lymphoma, perianal gland adenocarcinoma
what is adenocarcinoma?
a malignant tumor originating in glandular epithelium
what is the definition of inflammation?
a complex reaction of vascularized connective tissue in response to injury
what are the four physical components of the inflammatory process?
- plasma
- circulating cells
- blood vessels
- cellular and extracellular components of connective tissue
what six circulating cells are involved in inflammation?
- neutrophils
- lymphocytes
- platelets
- monocytes
- eosinophils
- basophils
what four non-circulating connective tissue cells are involved in inflammation?
- mast cells (from basophils)
- fibroblasts
- macrophages (from monocytes)
- lymphocytes
what two types of materials comprise the extracellular matrix surrounding the blood vessels in an inflammatory response?
- fibrous proteins (collagen, elastin)
- adhesive glycoproteins (fibronectin, laminin, etc.)
what are the three basic characteristics of acute inflammation?
- short duration (minutes to days)
- eduxation of fluid and plasma proteins (edema)
- emigraton of leukocytes (primarily neutrophils)
what are the three basic characteristics of chronic inflammation?
- occurs over a long period of time (days to years)
- mediated by lymphocytes and macrophages
- associated with proliferation of blood vessels and connective tissue
*** what are the five cardinal signs of acute inflammation?
- redness
- swelling
- heat
- pain
- loss of function
the escape of fluid, proteins, cells from the vascular system into interstitial tissue or body cavities
exudation
what is exudate?
inflammatory extravascular fluid with high protein concentration, much cell debris, and specific gravity above 1.020 (e.g. pus)
what is transudate?
extravascular fluid with low protein concentration (mostly albumin), specific gravity less than 1.012, few cells and debris
an accumulation of proteinaceous fluid in interstitial or serous cavities
edema
what are the four basic vascular changes in the process in acute inflammation?
1. immediately after injury: a transient vasoconstriction
2. then a vasodilation occurs (opening of arterioles and capillary beds)
3. blood flow to the tissue increases (redness)
- circulation slows (stasis) due to increased permeation of microvasculatutre (edema)
4. migration of leukocytes through the vessel walls
what are the five mechanisms for vascular leakage in inflammation?
1. endothelial contraction
2. junctional retraction
3. direct endothelial injury
4. leukocyte-dependent injury
5. endothelial regeneration
what causes endothelial contraction, where does it occur, what is the result, and how long does it last?
- histamine, bradykinin, leukotriene release
- occurs only in venules
- opens cellular gaps in the endothelium and vascular leakage occurs
- rapid and short lived (15-30 minutes)
what causes vascular leakage via junctional retraction? When does it start? How long does it last?
cytokines such as IL-1, TNF, and INF-gamma induce the cell to change its cytoskeleton and pull the cells apart at the junctions. Starts in 4-6 hours and lasts 24+ hours.
what stops vascular leakage upon damage to the endothelium when does it start, and how long does it last?
- thrombosis or repair of the endothelium
- death
- starts 2-12 hours and lasts for days (e.g. sunburn)
how do leukocytes lead to vascular leakage?
by the secretion of free radicals and proteolytic enzymes that cause cell damage
why does the process of angiogenesis cause leaky blood vessels?
the endothelial cells need to form junctions
what are the five steps of leukocyte extravasation?
1. rolling
2. activation
3. adhesion
4. diapedesis (transmigration across the endothelium)
5. chemotaxis (migration through the interstitium)
what are the three families of adhesion molecules?
1. selectins
2. immunoglobulins
3. integrins
what are selectins and what do they do?
proteins present on the surfaces of platelets, endothelium, and leukocytes that have binding sites for cell-surface oligosaccharides. This allows leukocyte and platelet adhesion to vascular endothelium during an inflammatory reaction.

P-selectin - endothelium and platelets
L-selectin - leukocytes
what are the two major types of immunogloublins involved in cell adhesion in the inflammatory process and to what do they bind?
1. ICAM-1 ("intracellular adhesion molecule")
2. VCAM-1 ("vascular cell adhesion molecule)

bind to endothelium and leukocyte integral proteins
what stimulates the redistribution of adhesion molecules to the endothelium during an inflammatory reaction and how do they work?
- histamine from mast cells
- thrombin from platelets
they trigger P-selectin release from Weibel-Palade bodies. This is a fast mechanism.

- IL-1, TNF
they initiatethe synthesis of new proteins and can take several hours
***what are the three steps in neutrophil migration in acute inflammation?
1. rapid rolling and loose adhesion mediated by selectins
2. activation by endothelium or chemotactins increases the neutrophil integrin avidity (receptor binding strength)
3. formation of stable bonds with endothelial cells (beta-2-integrin binds with ICAM-1)
where is the primary site and mechanism for leukocyte transmigration?
in the venules, leukocytes go through the endothelial cell junction and perforate the basement membrane with collagenase
what is the temporal distribution of leukocytes in an acute inflammation reaction?
- neutrophils predominate in the first 6-24 hours
- monocytes may predominate 24-48 hours
- mixed inflammatory reactions are common
what are the major chemotactic agents for leukocytes?
- bacterial products and necrotic debris
- complement (especially C5a)
- lipoxygenase derivatives (leukotriene B4)
- cytokines (especially IL-8)
what is the basic process of leukocyte chemotaxis to a site of inflammation?
1. cytokines bind
2. phospholipase C is activated
3. phosholipase C second messengers (DAG, IP3) alters the level of intracellular calcium
4. calcium change causes contractile elements to change cell shape
what biochemical processes are involved with leukocyte activation by chemotactic factors?
- production of arachadonic acid metabolites and phosoholipids
- degranulation and secretion of lysosomal enzymes
- oxidative burst
- modulation of adhesion molecules
*** what are the three basic steps of phagocytosis by leukocytes in inflammation?
1. recognition and attachment
2. engulfment
3. killing/degradation
what enhances phagocytosis by leukocytes?
opsonization:

- Fc fragment of IgG
- C3b
- CR3 (recognition of lipopolysaccharides in Gram negative bacteria) - endotoxemia
what chemicals are involved in killing of bacteria by leukocytes?
- oxygen derived free radicals
- hypochlorite
- other things
what are the major cells that make inflammatory mediators?
***hepatocytes
platelets, neutrophils, monocytes/macrophages, mast cells, endothelium
what are the three primary cellular preformed mediators that are stored in secretory granules?
- histamine
- serotonin
- lysosomal enzymes
which cellular inflammatory mediators are not stored, but must be synthesized.
- prostaglandins
- leukotrienes
- platelet activating factors
- activated oxygen species
- nitric oxide
- cytokines
what two basic types of inflammatory mediators are activated (primarily) by the liver?
- Factor XII (bradykinin, etc.)
- complement
what complement proteins are anaphylatoxins?
C3a and C5a
what are the actions of bradykinin?
- vasodilator
- smooth muscle contraction
- increases vascular permeability
- causes pain
- causes loss of function
what six major stimuli initiate mast cell degranulation?
1. physical injury (heat, cold, trauma)
2. immune reactions (e.g. IgE)
3. presence of anaphylatoxins (C3a, C5a)
4. activation by leukocytes
5. neuropeptides (e.g. substance P)
6. cytokines (IL-1, IL-8)
what are the two major effects of histamine in inflammation?
1. dilates arterioles
2. increases vascular permeability of venules
where is complement made, what is its primary function, and by what mechanism is it activated?
made in the liver to target microbes, it consists of about 20 proteins that are activated in sequence by a cascade of proteolytic reactions. One result is to form the C5b-9 MAC.
what endogenous and exogenous agents can activate complement?
- IgG, IgM
- microbial surfaces (polysaccharides)
- venom
- endotoxin (LPS)
- aggregated IgA
what is the action of C5a on leukocytes?
- chemotactic agent
- increases endothelial adhesion by increasing the avidity of integrins
what is the action of C3b and C3bi?
opsinization
what are the two pathways initiated by and the effects of Factor XII (Hageman factor)
1. kinin cascade - ultimately leads to fibrin degradation and complement activation
2. clotting cascade - ultimately leads to fibrin formation
what are the four plasma mediator systems and how are they interrelated?
what is the function of fibrinopeptides?
- increase vascular permeability
- chemotactic for leukocytes
what are the two primary clotting factors?
fibrin and thrombin
***what is the basic relationship between the fibrinolytic system and inflammation?
the act of clotting activates complement and promotes inflammation
what are the two inflammatory mediators that are metabolites of arachidonic acid, and what inhibits this process?
leukotrienes and prostaglandins. Corticosteroids inhibit the synthesis of arachidonic acid from membrane phospholipids and inhibit production of these inflammatory mediators.
what is the main pharmacologic action of NSAIDs?
inhibit the production of prostglandins via the cyclooxygenase pathway
what are the two pathways of production of inflammatory mediators from arachidonic acid and what are their end products?
1. cyclooxygenase pathway produces prostaglandins
2. lipoxygenase pathway produces leukotrienes
why do omega-3 fatty acids in the diet have an anti-inflammatory effect?
they incorporate into the cell membrane and are poor substrates for the cyclooxygenase pathway (prostglandins) and the lipoxygenase pathway (leukotrienes)
what are the primary actions of platelet activating factor (PAF)?
- increases vascular permeability
- stimulates aggregation of platelets
- stimulates the release of platelet derived mediators like serotonin
- stimulates leukocyte aggregation/adhesion
- chemotactic for leukocytes
- primes leukocytes for respiratory burst and degranulation
- boosts synthesis of eicosanoids (prostaglandins and leukotrienes)
what cell types are the primary producers of cytokines and what are the main cytokines involved in the inflammatory response?
produced by macrophages and lymphocytes.

IL-1, IL-8, and TNF
what six major effects do inflammatory cytokines have on the activation of endothelial cells
(all upregulate gene transcription)
- adhesion molecules
- other cytokines
- growth factors
- eicosanoids
- synthesis of NO
- induces procoagulant activity
what are the main actions of TNF?
- induces aggregation and the priming of neutrophils
- facilitates release of proteolytic enzymes from mesenchymal cells
how do cytokines form a bridge between acute and chronic inflammation?
they:
- increase fibroblast production
- increase collagen synthesis
- promote secretion of proteases that remodel connective tissue
- induce the synthesis of PGE by fibroblasts
in fulminant inflammatory reactions, what compounds can predominate?
lysosome enzymes. They can lead to granulomatous inflammation because they cause a massive chain-reaction of events and mass tissue destruction.
what primary inflammatory mediators produce (1) fever, (2) pain, and (3) tissue damage?
1. fever: IL-1, IL-6, TNF, prostaglandins
2. pain: prostaglandins, bradykinin
3. tissue damage: leukocytic lysosomal enzymes, oxygen metabolites, NO (free radicals)
how long after a non-infected incision will neutrophils be present at the wound margins? how long until epithelial layer is reformed?
24 hours; 48 hours
how long after a non-infected incision will neutrophils be replaced by macrophages? what also will be present?
by day 3. Granulation tissue forms in the incisional space.
how long after a non-infected incision will collagen fibrils begin to bridge the incision? what else happens around this time?
by day 5. Epidermal components begin to keratinize
what, in the wound, happens in the second week following a normally healing skin incision?
- collagen accumulation and fibroblast proliferation
- signs of inflammation disappear
- blanching/scarring
how does second intention healing differ from first intention healing?
- inflammatory response in second intention healing is more intense
- much larger amounts of granulation tissue are formed (second intention)
- wounds are closed by wound contraction - associated with MYOFIBROBLASTS
what are the six basic steps in wound healing
1. induction of acute inflammation
2. regeneration of parenchymal cells
3. migration of parenchymal and CT cells
4. synthesis of ECM proteins
5. remodeling of CT and parenchymal proteins
6. collagenization
how does Vitamin C promote wound healing?
it is a cofactor in the conversion of proline to hydroxyproline for the formation of procollagen
what is the major difference between procollagen and collagen?
procollagen, the procursor to collagen, is a water soluble polymer that is converted to insoluble collagen by proteolysis of its protein end-groups and cross-linking of its hydroxyl groups
what three types of physical/chemical stimuli promote collagen formation?
- growth factors (PDGF, FGF, TGF-beta)
- cytokines (IL-1, IL-4)
- phagocytic stimuli
what mineral is necessary for collagen remodeling?
zinc
what type of cells produce collagen remodeling enzymes?
fibroblasts, macrophages, neutrophils, synovial cells, some epithelial cells
how can the overproduction, underproduction, or resistance of (to) TGF-beta cause pathologic conditions?
- since TGF-beta is a growth inhibitor, underproduction/resistance can lead to tumor formation
- since TGF-beta stimulates fibroblast chemotaxis and collagen production, overproduction of TGF-beta can lead to a wide variety of pathologic fibrosis, particularly in the lungs, liver, and kidney
- since TGF-beta is an immunosuppressant, overproduction can lead to immunodeficiency and overproduction can lead to autoimmune diseases (IL-17 mediated)
after one week after incision, how much of the original tensile strength does skin have?
10%
what is the maximum amount of recovery of tensile strength in a skin incision and how long does this take to occur?
70-80% max after about 3 months
what six major factors inhibit wound healing?
1. nutritional deficiency (Vit C, Zinc, protein, metabolite)
2. glucocorticoids
3. infection
4. mechanical factors (non-union, wound dehiscence)
5. inadequate blood supply
6. foreign bodies
what is "proud flesh"?
excessive granulation tissue (perfused, fibrous connective tissue that replaces fibrin in a clot)
what is amyloidosis?
a disease processes characterized by deposition of a pathologic protein called amyolid into soft tissues, attributed to a malfunction of the immune system.
what is the secondary structure of amyolid protein?
beta pleated sheet; insoluble
generally, how does deposition of amyolid protein cause pathogenesis?
insoluble fibrils deposit next to blood vessels and interfere with nutrient exchange, causing cell death.
what are some clinical presentations of amyloidosis?
renal - azotemia, proteinuria, renal failure
hepatic - broad loss of functions
bowel - chronic diarrhea and wasting
**** what is the end product of coagulation?
fibrin
what are the four steps of fibrosis?
- formation of new blood vessels (angiogenesis)
- migration and proliferation of fibroblasts
- deposition of ECM
- maturation and organization of connective tissue (remodeling)
how long after inflammation does fibrosis begin?
24 hours; most active at 3-5 days
what are the four steps of angiogenesis?
- proteolytic degradation of BM of parent vessel
- migration of endothelium toward angiogenic stimulus
- proliferation of endothelium behind migrating front
- maturation and organization of endothelium
what is the function of metalloproteinases? what is the major metal at the enzyme center?
break down collagen in the extracellular matrix. Zinc is the major metal.
what is the most critical factor in inflammatory fibrosis and what cells produce it?
TGF-beta, which is produced by platelets and macrophages.
what is granulomatous inflammation?
distinctive type of chronic inflammation in which the predominant cell type is the EPITHELIOID CELL - an activated and structurally modified macrophage