DD Unit 2 Flashcards
major causes/etiologies of cell injury
a.Physical agents: trauma/heat
b.Chemical and drugs: drug toxicity, poisoning
c.Infection: pathogenic bacteria, virus, fungi, protozoa
d.Immunologic insults: anaphylaxis, autoimmunity
e.Genetic derangement: phenylketonuria, cystic fibrosis
f.Nutritional imbalance: atherosclerosis, protein and vitamin deficient
g.HYPOXIA: cells receive too little O2, causes: lung disease, heart failure, shock, arterial or venous thrombosis.
h.Injury from temperature extremes
heat stroke
hyperthermia
Hypothermia
Electrical injury
how cell injury leads to pathogenesis of disease
injury: non-lethal, physical damage or alteration of normal
perturbed cell can’t perform: metabolize nutrients, synthesize needed produce -> illness
most injury leading to disease = epithelial injury- 1st tissue to encounter environment
injury to one tissue typically affects other adjacent ones
morphologic changes from cell injury that cause signs and symptoms of disease
symptoms: complaints voiced by patient
signs: abnormal findings observed by MD
injury commonly changes:
cell membranes- lipid in membrane is easily oxidized and supports oxidative chain rxn; membrane damage harms ion pups; leads to cell swelling from inc Na+ and H2O
mitochondria- inc in H2O and dec in O2-dependent synthesis of ATP required to fuel ion pumps
endoplasmic reticulum- cistern are distended and polyribosomes detach; dec in protein synthesis
nucleus- altered appearance; probably affects rRNA synthesis, causing dec in protein synthesis
free radicals, how they arise, how they produce injury, how they’re eliminated
chem species w/ unpaired e-
chemically damage proteins, DNA, RNA, trigger lipid peroxidation in membranes
generated by intrinsic oxidases (in ER of all cells and in PMNs) and radiation, esp in high pO2
superoxide O2- can be removed via superoxide dismutase
remove free radicals:
- antioxidants: uric acid, Vit E, etc
- catalase
- glutathione peroxidase
how hypoxia/ischemia makes free radical damage an important cause of cell injury
hypoxia: cell receives too little O2
ischemia: lack of O2 from poor blood perfusion (worse than HPX- cells aren’t getting O2 or nutrients)
HPX leads to ischemia
HPX:
insufficient ATP production; ROS following O2 therapy
acute inflammation- PMNs have ROS-producing enzymes
reperfusion of HPX tissue- produces ROS after HPX is corrected
necrosis vs apoptosis
necrosis: mostly commonly seen with ischemia; problem with blood flow; many cells die at once
signs- elevation of intracellular Ca2+, no ATP synthesis, release lysosomal hydrolyses, swollen cytoplasm; DNA fragmentation
apoptosis: programmed cell death of individual cells; highly regulated w/ surface binding receptors Fas/CD95; mito switch caspases and endonuclease; cells shrink; large membrane blebs; uniformly compact and dense DNA; patterned DNA breakage
adaptations associated with chronic injury
chronic hypertension- cells may hypertrophy (L ventricle working harder; needs more mito)
cells may atrophy when func is less needed- (gross muscle atrophy in a cast)
metaplasia- chronic mechanical stress (cigarette smoke replacing one cell type for another)
hyperplasia- inc in # of cells; when adrenal cortical cells increase in number after tumors produce ACTH-like polypeptides
4 major types of necrosis
coagulative- dead cells are ghost-like remnants of former selves; common in MI; chromatin clumps and causes pyknosis; removal of chromatin is then called karyolysis
liquefactive- dead cell dissolves away as lysosomal hydrolyses digest cell components; most common in brain and spleen
caseous- THINK TB; central portion of infected lymph node is necrotic and has chalky white appearance
fat- necrotic adipose tissue that develops after acute pancreatitis or trauma; fats are hydrolyzed into free fatty acids which precipitate Ca2+ producing “peculiar” chalky grey material
reversible and irreversible alterations during hypoxic injury
reversible: dec ATP dec Na+ pump (swelling) dec protein synthesis inc glycolysis, dec pH
irreversible:
inc Ca2+ influx
DNA and protein degradation
activation of lysosomal enzymes
acute vs chronic inflammation
onset
cellular infiltrate
tissue injury, fibrosis
local and systemic signs
acute: fast; min/hrs mainly NEUTROPHILS/PMNs usually mild and self-limited prominent --innate immunity; exudation of fluid and plasma proteins (edema); emigration of leukocytes
chronic: slow; days MACROPHAGES, monocytes and lymphocytes often severe and progressive less --adaptive immunity; more tissue destruction; proliferation of RBCs, deposition of CT
classic clinical signs of inflammation
local and systemic
local: redness- rubor heat- color swelling- tumor pain- dolor loss of function vasodilation vascular permeability swelling from mediators/pressure on nerves
systemic: sleepiness/grogginess anorexia fever high WBC count blood pressure alterations
transudate and exudate
transudate:
inc hydrostatic pressure/ reduced oncotic pressure
low specific gravity
low total protein
exudate:
inflammation
inc specific gravity
inc total protein
TLRs and inflammation
microbes breach barrier; TLRs recognize and initiate response
potential outcomes of inflammation
best to worst:
complete resolution
(macrophage cleans up necrotic debris; tissue regeneration; lymphatic drainage decreases edema)
scarring ("patch" not 100% functional)
abscess formation (wall off infection)
progression to chronic inflammation
collateral tissue damage associated with inflammation
Nofsinger’s bomb analogy
inflammation- tissues get damaged
cells responsible for damage:
leukocytes (once they’re activated they don’t differentiate between offender and host)
neutrophils and macrophages (produce ROS, NO, and lysosomal enzymes) within phagolysosome- released into ECF and causes damage
cytokines- recruiting leukocytes
granulomatous inflammation
specific type of chronic inflammatory rxn characterized by accumulation of modified macrophages, giant cells, lymphocytes, and occasional plasma cells
initiated by variety of infectious/noninfectious agents
occurs in presence of poorly digestible irritants
ex: bac (TB, leprosy, syphilis) parasitic (schiostomiasis) fungal inorganic metal/dust (silicosis, berylliosis) foreign body (suture) sarcoidosis (unknown etiology; non-necrotizing) Crohn's disease (non-caseation)
typically don’t see neutrophils
cytokines and systemic responses
cytokine rxns responsive of systemic manifestations of acute inflammation
bacterial products (LPS) and inflammatory stimuli lead to cytokine production; then systemic effects
key mediators:
cytokines TNF, IL-1, IL-6
findings:
fever
acute-phase proteins
leukocytosis
role of Hageman factor in systems (Factor XII)
activation of Hageman factor by exposure to collagen/basement membrane in setting of inc vascular permeability, leading to 3 pathways below:
coagulation pathway (activate thrombin)
Factor XII via intrinsic pathway- activates clotting cascade; activates thrombin to convert fibrinogen to fibrin; clot formation
thrombin also binds PARs protease activated receptors
thrombin promotes formation of prostaglandins, cytokines, nitric oxide, PAF
fibrinolysis pathway (activate plasmin)
goal is to degrade fibrin
plasminogen is activated to form plasmin, which cleaves fibrin to form fibrin degradation products;
increases vascular permeability and activates C3 to C3a
activation of kallikrein/Kinin system-
pre-kallikrein converted to kallikrein protease; activates kininogen to bradykinin
this process activates C3 to C3a
leads to vasodilation, inc vascular permeability, bronchial smooth muscle contraction, and PAIN
kinin system quickly inactivated by kinases
features of repair processes
macrophages play central role in repair
-clear offending agents, provide growth factors, secrete cytokines
repair begins w/in 24 hrs; emigration of fibroblasts for proliferation phase; proliferation of fibroblasts (produce collagen and EC matrix) and endothelial proliferation (neovascularization)
3-5 days later specialized granulation tissue formation; scar (via epithelial cells- epidermis, mucosa) (liver regenerates)
granulation tissue and its components
new CT and blood vessels that form on surface of wound during healing; forms EC matrix
a response to injury
part of scar formation
fibroblasts come in and form collagen
endothelial cells neovascularize
macrophages remove waste
typically don’t see neutrophils
repair of epithelium
re-epithelialization via:
adjacent cells, bulge stem cells (deep) and epidermal stem cells
stem cells line along follicle; start to regenerate deep;
epidermal stem cells in skin regenerate epithelium
liver regneration
remarkable regernation capacity
2 mechs:
-proliferation of remaining hepatocytes
-repopulation from progenitor cells
proliferation- triggered by cytokines and protein GFs
- priming phase: IL-6 produced by Kupffer cells make parenchymal cells able to receive/respond to growth factor signals
- Growth Factor phase: HGF and TGF-alpha stimulate cell metabolism and cell cycle; almost all hepatocytes replicate; followed by nonparenchymal cells
- hepatocyte replication phase: same as GF phase
- termination phase: hepatocytes return to quiescence
if proliferative capacity is impaired: liver regenerates from progenitor cells
scar formations
normal
hypertrophic
keloid
contracture
fibrous tissue (fibrosis) that replaces normal skin after injury
hypertrophic- raised scar; growing beyond boundaries of injury, but REGRESSES
keloid- raised scar, growing beyond boundaries of injury; NO REGRESS/REMODEL/CONTRACT
contracture- result of a contractile wound-healing process occurring in a scar that has already been re-epithelialized and adequately healed
local and systemic factors influencing repair/regeneration process
local:
infection
persistence of insult (Hep C and alcohol)
trauma- early movement prior to complete repair
trauma- foreign material
size/location
systemic: nutritional (impairs collagen synthesis) -protein deficiency -Vit C deficiency metabolic- delay repair -diabetes glucocorticoids: inhibit collagen synthesis vascular: ischemia, venous drainage arteriosclerosis and atherosclerosis venous drainage impairment: varicose veins
5-lipoxygenase and COX-1 and COX-2
5-lipoxygenase: critical enzyme in pathway for production of leukotrienes from arachidonic acid
COX-1 and COX-2 are critical for prostaglandin formation
critical for acute inflammation response
COX-1 vs COX-2
expression tissue locale physiologic role inducers inhibitors
COX-1
constitutively
GI, platelets, kidney, vascular smooth muscle, bone
inc aggregation, inc renal blood flow, vasodilation/cons, bone form/resorb
baseline levels of activity at all times
actions diminished by NSAID use
COX-2
as needed, in inflamed tissue
areas of pain, hypothalamus, fever, kidney, endothelia, uterine SM, ductus arterioles
enhance edema, heat, stress, vasodilator, anti-aggregators to platelets, inc contractions
IL-1, IL-2, INFgamma, lipopolysaccharides, shear stress, growth factors
diminished by NSAID use
effects of prostaglandins on:
vascular smooth muscle: PGE2/I2 causes vasodilation
TXA2 causes vasoconstriction
platelets: TXA2 has pro-aggregators effect
GI tract smooth muscle/secretory cells: PGE2/PGI2 inhibit HCl secretion, increase mucous secretion, inc smooth muscle contractions
kidney: PGE2/PGI2 increases renal blood flow, promotes diuresis
uterus: PGF2a/E2 induces contractions
inflammatory cells: PGE2/PGI2 potentiate pain, edema, fever
NSAIDs that inhibit COX-w would possess therapeutic actions (pain, fever, inflammation relief)
-potential side effects: acute renal failure, thrombototic events, prolonged gestation
inhibiting COX-1 produces potential side effects of GI ulceration and prolonged bleeding time, and acute renal failure
effects of leukotrienes on inflammatory cell func and pulm/vascular smooth muscle
LTB4: neutrophil chemotaxis, aggregation, and transmigration through endothelium
LTC4/LTD4/LTE4: inc vascular permeability, bronchoconstriction, vasoconstriction
-important in pathophys of asthma, psoriasis, arthritic/allergic/hypersensitive processes
interaction of prostacyclin and thromboxane A2 related to vascular smooth muscle and platelets
thromboxane effects:
vascular smooth muscle- constriction (mainly in platelets)
platelets- aggregation
prostacyclin effects (opposite): vascular smooth muscle- dilation (mainly in endothelium) platelets- disaggregation
effect on COX 1 and 2
aspirin
acetaminophen
NSAIDs
COX-2 selective inhibitors
effect on COX
therapeutic use
adverse rxns
Aspirin:
1 and 2 irreversible
analgesic, antipyretic, anti-inflammatory, antithrombotic
GI irritation, inc bleeding, allergy, avoid if flu, pregnant, renal insufficiency
acetaminophen:
neither
analgesic and antipyretic properties; not a true NSAID
less GI symptoms, CNS COX2
NSAIDs
1 and 2 reversible
analgesic, antipyretic, anti-inflammatory, antithrombogenesis
GI, bleeding, renal failure/nephritis, low uterine contractions, inc MI, inc stroke
COX-2 selective inhibitors
2 reversible
analgesic, antipyretic, anti-inflammatory
less GI, inc MI, inc stroke (due to platelet comparaggregation)
aspirin at low doses is able to exert anti-thrombotic/cardioprotective effect
vs COX2 selective agents:
aspirin is irreversible COX-1 and 2 inhibitor
@ low doses: active aspirin concentrates in hepatic portal vein; selective inhibitory effect on platelet COX1 and endothelial COX2; preferentially inhibitory effect on COX1; blocks pro-clotting COX1 = antithrombotic effect
COX1 selective bc as soon as COX2 is knocked out, body starts making more faster; gives you temporal advantage
@ high dose:
no conc gradient is generated between platelet and endothelial; balance each other out; no effect
COX-2 selective agents:
COX2 is expressed to prevent clotting
inhibiting COX2 allows COX1’s pro-aggregation to increase thrombus formation
no COX2 = clotting
therapeutic uses metabolism/excrete common side effects overdose toxicity contraindications D-D interactions
aspirin
acetaminophen
ibuprofen
celicoxib
aspirin:
analgesic, antipyretic, anti-inflame, antithrombotic
Phase 2, renal
GI irr, bleeds, allergies
severe acidosis
avoid when flu, pregnant, renal insufficiency
phenytoin, Warfarin, alcohol, Lithium
Acetaminophen: analgesic, antipyretic Phase 2 inc hepatic enzymes, CNS madness liver damage can take when pregnant alcohol induces formation of hepatotoxic metabolite
ibuprofen:
analgesic, antipyretic, anti-inflammmatory
hepatic, renal
GI (less than aspirin), reversible platelet effects
–
pregnant
–
Celicoxib:
analgesic, antipyretic, anti-inflame, reversible inhibit of COX2
hepatic, renal
renal, CV events, better for GI and platelets
–
pregnant
Warfarin-inc bleed chances
regulation of glucocorticoid secretion by hypothalamic-pituitary-adrenal gland axis
3 modes of regulation:
diurnal rhythm
-sleep/wake cycles; hypothalamus release CRH; anterior pituitary releases ACTH; cortisol release
negative feedback
- circulating corticosteroids; regulates (neg feedback) on hypothalamus and pituitary; dec ACTH release + steroidogenesis
- chronic pharmacologic doses of glucocorticoids can suppress HPA axis; adrenal atrophy and insufficient adrenal response (neg feedback)
stress-
hemorrhage, severe infection, surgery, hypoglycemia, cold, pain, fear; overrides negative feedback; anterior pituitary releases ACTH; cortisol releases
effects associated with glucocorticoids and adverse effects when use as pharmacotherapeutic agents
glucocorticoids are used in inflammatory-type disorders incl: allergic rxns, collagen-vascular probs, eye disease, GI disease, hematologic disorders, neurologic disorders, pulm disease, skin disease, hypercalcemia, mtn sickness
adrenal crisis, hyperglycemia-diabetes like states, tissue breakdown and muscle wasting, atrophy of skin and CT, centripetal obesity
mineralocorticoid effects: inc absorption of Na, more secretion of H+ and K+, hypertension, edema, hypokalemia, metabolic acidosis
