Pathology E1 Flashcards
Reversible changes
hypertrophy, hyperplasia, atrophy, metaplasia, dysplasia
hypertrophy
inc in cell size, no new cells
(tissues with cells NOT capable of rep)
due to inc func demand/gfac/hormonal stim (activated growth factors, ion channels, oxygen supply, etc).
can co-exist w/ hyperplasia
Pathologic hypertrophy exp.
increased workload
hypertension
cardiocyte hypertrophy
Physiologic hypertrophy exp.
increased workload
pumping iron
skeletal muscle cell hypertrophy
Hyperplasia
inc in cell # –> inc in tissue/organ mass
(tissue with cells CAPABLE of rep)
exp. proliferation from stem cells, physiologic/pathologic hyperplasia
often co-exists w/ hypertrophy
Pathologic hyperplasia exp.
benign prostatic hyperplasia
Physiological hyperplasia
rapid growth via cell division in endometrial glands/stroma during proliferative phase of menstruation
hyperplasia + hypertrophy exp.
uterus during pregnancy
Atrophy
reduced cell size/organelles (long-term –> also dec in cell #)
dec workload/metabolic activity/protein synthesis
inc pro degrad
inc autophagy
via ischemia, denervation, aging, hormone withdrawal (mammary gland during menopause)
Metaplasia
Replacing cell types
Often adaptive response to stress
Via reprogramming stem cells
exp. respiratory epithelium in smoker (columnar to squamous), barrett’s esophagus during acid reflux (SSNKE –> intestinal columnar)
Dysplasia
Disordered growth/maturation
Response to persistence of injurious influence
*usu regresses upon removal of stimulus
Shares cytological features w/ cancer
exp. cervical dysplasia (SSKNE –> disordered)
General mechanisms of cell injury
- ATP prod/depletion
- Irrv. mitochondria damage (leakage of apoptotic proteins)
- Entry of Ca (inc mito perm, activ of cell enzymes)
- Oxygen/free radicals
- Defects in memb permeability
- Protein misfolding/DNA damage
Hypoxia vs ischemia
hypoxia–> dec oxygen (Low pO2 in blood), anaerobic E prod can continue
ischemia–> dec oxygen AND substrates (Mechanical obstruction of blood flow), aerobic/anaerobic compromised
Progression of ischemic cell injury
onset
reversible
irreversible
reperfusion injury (inc ROS formation, inflammation, Ca2+ mobilization)
Reversible cell injury (volume)
temporary loss of volume and E regulation
- Altered membrane permeability (Na+, Ca2+, water influx; K+, Mg2+ efflux). Cell swells
- inc wet weight of tissue, dec dry weight
- Small molecule leakage and intracellular acidification
- TEMPORARY loss of selective permeability
Reversible cell injury (Energy)
Drop in oxygen…
-ATP depletion, inc anaerobic metabolism (dec glycogen stores, inc lactic acid and Pi –> dec intracellular pH –> dec enzyme act)
-Ribosome detachment from RER
Dec protein synthesis
Reversible cell injury (Morphology)
Light microscopy
- Cell swelling –> hydropic change (vacuolar degeneration) –> lighter staining
- Some chromatin clumping
EM
-inc h2o, dilation of ER, dec glycogen stores, condensed mito, PM blebbing, blunting microvilli, myelin figures
Irreversible cell injury
- perm loss of selective permeability
- lg molecule leakage (troponin)
- inc anaerobic metabolism (inc glycolysis, inc lactate, dec pH)
- MPTP (high conductance), leakage
- membrane abnormalities –> cytochrome C leakage
Serum signs for irreversible cell injury
troponin
myoglobin
CK-MB isoenzyme
lactase dehydrogenase
Irrev cell injury (morphology)
Light
- Pyknosis: Nucleus shrinks
- Karyolysis: Nuclear degen, “halo.” (basophilia fades)
- Karyorrhexis: Nuclear fragments.
EM
matrix granules
flocculent densities
swelling/rupture
Ischemia/reperfusion injury
cell death after reestab blood flow
- oxidative stress
- more Ca flow (myocyte hypercontracture)
- wbc accumulation (Ab deposit, complement activation, etc)
MPTP
Uncoupling of oxidative phosphorylation by mitochondrial permeability transition with release of cyt. C to cytosol. (inc [Ca2+]in will cause mitochondrial damage)
*irreversible injury
cytochrome C
pro-apoptotic
Calcium homeostasis
[extracellular Ca] > [intracellular Ca]
- Intracellular Ca sequestered in mitochondria or ER
- maintained by Ca2+/Mg2+ ATPase
Injury –> inc cytoplasmic Ca –> inc damaging enzymes (phospholipases, proteases, endonucleases, ATPase) and opening of MPTP
Injury –> inc cytoplasmic Ca (preferentially taken up by mito) –> depleted ATP prod
Generation of ROS
Formed from UV/X-rays, enzymatic action (CCl4), O2 reaction with free transition metals, nitric oxide
Defenses against ROS
-Metal binding proteins (transferrins, ferritin, lactoferrin)
-Antioxidants (Vit A, C, E)
-Enzymes (SOD, glutathione peroxidase, catalase)
Fenton Reaction
damage by ROS
- Lipid peroxidation (attacks double bonds –> propagation and membrane damage) *vit E halts
- Oxidative protein modification (inc proteasomal degradation, disulfide linkage)
- genetic lesions (ss/dsDNA breaks)
- Ca influx
Func of SOD, glutathione peroxidase, catalase to remove ROS
SOD (O2 rad –> H2O2)
Glutathione peroxidase (OH rad –> H2O)
Catalase (in peroxisomes)
Glutathione peroxidase ratio
Indic cell’s ability to detoxify ROS
Oxidative stress …
[oxidized glutathione]>[reduced glutathione]
(GSSG>GSH)
CCl4 –> free radical mediated cell injury
CCl4 + e –> CCl3- + Cl-
CCl3- –> highly reactive free radical –> lipid per oxidation, membrane damage, FA change and necrosis in liver
Autophagy
cell “self-eating”
- controlled (ATG) and selective
- adaptive mech during stress/damage/development/diffrentiation
- failure –> accumulation of cell damage/aging
Autophagy process
Initiation Form phagopore (isolation membrane) Form autophagosome (double membrane) Fusion w/ lysosome Form autophagolysosome Degrade/reuse contents
Fenton reaction
OH radicals formed from H2O2 by converting Fe3+ to Fe2+.
Necrosis
- “accidental cell death”
- caused by irreversible cell injury
- morphologic changes following cell death, resulting from denaturation/enzymatic digestion of lethally injured cell
- ALWAYS pathologic
- clear INFLAMM. RESPONSE
Coagulative Necrosis
Most common (exp. ischemia –> infarct)
- enzyme digestion/protein denaturation
- tissue architecture intact but eosinophilic/anucleate (“ghost-town”)
- phagocytes remove the debris
Caseous necrosis
- “cheese-like” necrotic region
- pink granuloma w/I distinct inflamm border
Comm w/ TB (granuloma with eosinophilic center, surr by macrophages (epithelioid cells), multinucleated giant cells and lymphocytes
Liquefactive Necrosis
Whole cell digestion to viscious pus (removed by phagocytes)
- some focal bacteria/occas fungal infec
CNS –> hypoxic death (infarcts of the brain) –> liquefactive necrosis
Fat necrosis
focal fat destruction comm due to release of pancreatic lipases into substance of pancreas/peritoneal cavity (acute pancreatitis)
TAGs–> FFAs saponify with Ca –> chalky spots
Fibrinoid necrosis
Result of immune-complex (Ag-Ab) deposition in small blood vessels combining with fibrin to cause necrotic vasculitis
Lipid accumulation
Usu involves liver
small droplets –> coalesce to vacuoles –> push nuclei to periphery
atherosclerosis
CHL/CHL esters in cytoplasm of smc and macrophages in tunica intimacy of aorta and large arteries
Niemann-pick disease (C)
lysosomal storage disease w/ defective enzyme involved in CHL trafficking. CHL accumulation in multiple organs
In disorders with high blood levels of CHL, _______ store CHL. When these cells accumulate in subcutaneous tissue, they form _______.
In disorders with high blood levels of CHL, macrophages store CHL. When these cells accumulate in subcutaneous tissue, they form xanthomas.
Hyaline Change
Histologic term, not a specific marker
Accumulation of homogenous, glassy, eosinophillic substance in cells
Intracellular: Russell bodies, alcoholic hyaline
Extracellular: hyalinized walls of arterioles
Alcoholic Hyaline
Accumulation of keratin intermediate filaments in fatty liver (mallory bodies)
Abnormality in either glucose or glycogen metabolism
excessive intracellular deposit of glycogen (exp. DM - accumulation in renal tubular cells, hepatocytes, heart muscle cells and beta cells)
Lipofuscin
Insoluble byproduct of lipid peroxidation; sign of oxidative stress
Composed of lipid-containing residues of lysosomal digestion
- ‘wear-and-tear’ pigment, seen in everyone, accumulates with age
- yellow-brown
Hemosiderin
Hb-derived (Fe containing); systemic buildup causes hemosiderosis (not assoc w tissue/organ damage)
(inherited hemochromatosis–> if accumulated in heart, pancreas or liver can cause fibrosis, heart failure and diabetes.)
-golden yellow/brown, granular/crystalline
xs iron –> ferritin (Fe + apoferritin) forms hemosiderin granules
Dystrophic Calcification
Normal Ca2+ metabolism and serum Ca2+
- pathologic calcification
- found in nonviable/dying tissues
- exp. atheroma, damaged heart valves, TB lymph nodes etc.
- can cause organ dysfunction
Ca deposition as fine, white granules (basophilic, amorphous) found in necrotic tissue, valvular dysfunction and atheromas.
Metastatic Calcification
Abnormal Ca2+ metabolism, high serum Ca2+ (hypercalcemia)
Comm hypercalcemia causes: hyperparathyroidism, bone destruction, vitamin D deficiency, or renal failure.
Normally found: GI mucosa, kidneys, lungs, vasculature
Sim morphology to dystrophic calcification
Ionizing radiation
XR, gamma rays, particulate radiation
enough E to completely eject e- from atom that absorbs radiation “ionization”
Non-ionizing radiation
UV (when absorbed can result in excitation of molec/dimer formation)
cannot eject e- on affected atoms but can raise them to higher orbital states
exp. pyrimidine dimers on DNA
O2 Effect
Increased response to radiation in presence of oxygen (“normoxic” envio) (formation of perhydroxy radicals)
Damaged prostate/bone –> elevated enzymes in blood?
acid phosphatase (AcP)
Damaged cardiac muscle –> elevated enzymes in blood?
creatine kinase (CK), MB isoform aspartate transaminase (AST) lactate dehydrogenase (LDH)
Damaged liver –> elevated enzymes in blood?
aspartate transaminase (AST) alanine transaminase (ALT)
- AST –> substance abuse, EtOH
ALT–> liver disease (hepatitis, viral damage)
Damaged striated muscle –> elevated enzymes in blood?
creatine kinase (CK), MM isoform
Damaged pancreas –> elevated enzymes in blood?
lipase
Damaged pancreas/ovary/salivary glands –> elevated enzymes in blood?
amylase
Damaged liver/bone/intestine/kidney/placenta –> elevated enzymes in blood?
alkaline phosphatase (ALP)
General morphology of necrosis
- inc eosinophilia, blebbing, swelling, nuclear changes (pyknosis, karyorrhexis, karyolysis)
Necrosis mechanism of cell death
- cell death via swelling, dec ATP, inc membrane perm, release of macromolecules autolysis, INFLAMMATION
- 2 concurrent processes: enzymatic digestion and denaturation of proteins
- involves number of cells
- irrev loss of homeostasis
Morphology of coagulative necrosis
- cell swelling
- organelle swelling
- chromatin clumping
- membrane damage
- nuclear changes (enucleate cells)
- inflammation
Apoptosis
cell deletion by fragmentation into membrane-bound particles that are phagocytosed by other cells
E dependent
NO immune response triggered
Causes of apoptosis
embryogenesis hormone dependent involution in proliferating populations in tumors in immune/inflammatory responses in atrophy in viral diseases in response to injurious stimuli
Morphology of apoptosis
cell SHRINKAGE chromatin condensation cytoplasmic blebs and apoptotic bodies phagocytosis of apoptotic cells and bodies little/no inflammation
Features of apoptosis
Extrinsic/intrinsic activation Suppressors/promoters Caspase activation/proteolytic cascade Endonucleases, DNA ladder Fragmentation (apoptotic bodies) Phagocyte recognition (phosphatidyl serine --> eat me)
Exp of intracellular accumulation due to metabolic rate being too low for adequate removal
fatty liver (steatosis) CHL and CEs
Intracellular accumulation due to buildup bc of too slow metabolic rate/ or if cannot be degraded normally
Russel Bodies in plasma cells
Alpha 1 antitrypsin deficiency Alzheimer disease
Amyloidosis
caused by defects in synthesis, folding, transport, secretion
Lysosomal storage diseases
accumulation of endogenous materials
exp. Gaucher’s Disease (defect in glucocerebrosidase causing buildup of glucosylceramide)
Intracellular accumulation of exogenous substances
Exp. carbon buildup in lung
Endogenous pigment accumulation
Exp. Hemosiderin (one of major storage forms of iron)
Electromagnetic spectrum and its ability to prod bio effects
UV/XR/gamma rays, etc
Shorter wavelength
- higher frequency
- greater photon E
- greater ability to prod bio effects
Critical difference between non-ionizing and ionizing radiation
Dif size of individual packet of E and NOT total E involved
Non-ionizing: size packet enough to raise e- to higher level
Ionizing: size packet lg enough to eject one or more e- from absorbing molec
Critical target of radiation
damages to DNA
Indirect action of ionizing radiation
radiation interacts with other atoms or molecules (esp. WATER) to prod free radicals –> damage critical targets
^dominant effect of XR/gamma-rays
Direct action of ionizing radiation
radiation itself hits DNA molecule and produces damage to DNA molecules
^dominant effect of particulate radiation (neutrons/alpha particles)
Effects of radiation on cells
- Damage repaired completely
- Damage exceeds repair capability –> dies via necrosis or apoptosis
- Irreparable damage –> reproductive death of cell
- Damage –> gene mut –> cancer
- Damage –> gene mut (heritable)
The oxygen effect
Hypoxic cells –> more resistant to radiation than normoxic cells
After radiation, most cells tumor are hypoxic.
Reoxygenation –> mix of aerated/hypoxic cells present in tumor
Tx: More effective cell killing w/ mult doses (FRACTIONATION)
2 factors that dictate which cells are most affected by radiation
- Cell cycle (M phase most sensitive, then G2, G1) (S phase, most resistant)
- Cell type
resistant: mature cells, more differentiated
sensitive: stem cells, younger, higher metabolic activity, higher prolif/growth rate
fetus>child>adult
Early effects of ionizing radiation
NO specific morphological changes. Change same as those due to ischemia/toxins/cell injury
- occur in hrs-weeks
- dep on cell cycle
- cell death via necrosis/apoptosis
- acute inflammatory response
- early vascular injury, not very specific
- presence of hyaline deposits –> thought to initiate delayed phase of radiation injury
Delayed effects of ionizing radiation
Mostly due to vascular consequences
- degenerative/reparative, involve any organ/tissue
- DAMAGE TO MICROVASCULATURE
- collagen hyalinization + tunica media thickening
- narrowing/obliteration of vascular lumen
- chronic ischemia –> parenchymal degeneration
-FIBROSIS (occurs later, comm in cancer therapy)
Nonneoplastic complications of radiation
cataracts, myocardial fibrosis, constructive pericarditis, esophogeal structure pulmonary fibrosis stricture of small intestine nephritis transverse myelitis congenital malformations sterility radiodermatitis
Effects of UV light
UV=non-ionizing, a human carcinogen
SKIN (premature aging, cancers)
EYES (cataract risk)
REDUCED IMMUNE RESPONSE
Mitochondrial (intrinsic) pathway of apoptosis
Initiated by cell injury –> BCL2 –> caspase activation
Death receptor (extrinsic) pathway of apoptosis
Initiated by receptor-ligand interactions (FAS, TNF) –> caspase activation
Consequences of mitochondrial dysfunction cumulating in cell death by necrosis
dec O2 supply, toxins, radiation –> mito damage/dysfunction –> dec ATP gen, inc prod ROS –> multiple cell abnormalities –> necrosis
Consequences of mitochondrial dysfunction cumulating in cell death by apoptosis
dec survival signals, DNA, protein damage –> inc pro-apoptotic proteins –> leakage of mitochondrial proteins –> apoptosis
ACUTE vs CHRONIC INFLAMMATION immune response
ACUTE - innate
CHRONIC - adaptive (cellular and/or humoral)
Acute inflammation etiology
Physical injury, ischemia, Gram negative or positive bacteria
Chronic inflammation etiology
Fungi, mycobacteria, parasites
Autoimmune diseases
Acute inflammation characteristic features
- Tissue necrosis
- Vascular changes
- Fluid and cell exudation:
neutrophils followed by
macrophages
(early/resolves)
Chronic inflammation characteristic features
local expression of an ongoing immune response
- Cellular infiltration: Lymphocytes, macrophages, plasma
cells
-special form = the GRANULOMA
- Can be simultaneous with tissue necrosis, acute inflammation, and repair and regeneration
(late/persistent)
Causes of chronic inflammation
PERSISTENT INFECTIOUS PATHOGENS (viruses, bacteria, fungi, parasites)
Immune responses (to foreign antigens (HS rxns), to self-antigens (AI diseases))
Rxns to non-degradable foreign bodies
-exogenous
-endogenous
(^mostly innate response)
Intracellular Vesicular pathogens and immune response
Bacteria fungi, protozoa
Activates CD4+ Th1 cells and macrophages.
Intracellular cytoplasmic pathogens and immune response
Viruses, bacteria, protozoa
Activates CD8 T cells. NK cells, NKT cells
gamma-delta cells.
Extracellular Interstitial space/blood.lymph pathogens and immune response
Viruses, bacteria, spirochetes, protozoa, fungi, worms
Activates CD4+ Th2 cells, B-cells (release IgG via plasma cells), phagocytes and the complement system. Note parasites will also attract eosinophils.
Extracellular Epithelial surfaces pathogens and immune response
Bacteria, worms
Activates CD4+ Th2, Th17 cells, B-cells (release IgA via plasma cells)
Chronic inflammation w/ INTRACELLULAR VESICULAR pathogens - THE CD4 Th1 CELL RESPONSE
Macrophages use PRRs to sense invading pathogens –> MHC II and costimulatory molec expression, IL12 stim TH1 –> present antigen to T cells, which further activate macrophages by secreting IFN-gamma
(M1-type macrophage - PROINFLAMMATORY)
Inc phagocytosis, degradative lysosomal enzymes
Enhanced killing –> Reactive N and O species/bacteriostatic peptides
Prod of proinflammatory cytokines, derivatives of arachidonic acid, growth factors
(CD4 TH1 activated macrophages) Pathology Lymphocytes Macrophages (multinucleated giant cells) Granuloma formation Fibrosis (scarring)
Pathogens: TB Leprosy (tuberculoid) Deep fungal diseases Leishmaniasis (cutaneous)
Chronic inflammation w/ intracellular vesicular pathogens - THE IMPAIRED CD4 Th1 CELL RESPONSE
Impaired macrophage bacteriolytic function
(treg, no IL12, so no T cell stim)
(M2 macrophage - ANTIINFLAMMATORY) No reactive N and O species, Prod of IL-10 Profibrotic, angiogenic growth factors: aid in wound healing ^non-killing, more healing
No costimulation T regulatory cells
Pathology:
Macrophages containing microorganisms
No granuloma formation
Pathogens Lepromatous leprosy
Visceral leishmaniasis
Chronic inflammation w/ intracellular cytoplasmic pathogens - the CD8 response
Cd8 T cell –> target cell death…
- -> perforin, granzymes, Fas L
- -> IFN-gamma, TNF-alpha, TNF-beta
Pathology:
Cell/tissue necrosis
Lymphocytes
Macrophages
Exp.
Viral diseases (vaccinia, influenza, rabies, hepatitis)
Listeriosis
Chronic inflammation w/ extracellular (interstitial/blood/lymph) pathogens - THE CD4 Th2 CELL RESPONSE
Activates CD4+ Th2 cells (–> IL-4, IL-5, IL-13), B-cells (release IgG via plasma cells), phagocytes and the complement system. *Note parasites will also attract eosinophils via IL-5
- Activation of B cells secreting Ab to eliminate extracellular pathogens and neutralize toxins
Pathology: Lymphocytes, plasma cells Neutrophils, EOSINOPHILS Macrophages (M2) Fibrosis (scarring)
Exp. Pyogenic cocci (exp. chronic appendicitis. pyelonephritis) Spirochetes Toxins Parasites syphilis
Chronic inflammation w/ EXTRACELLULAR pathogens (EPITHELIAL surfaces) - THE CD4 Th17 CELL RESPONSE
NEUTROPHIL recruitment and activation (via IL-17, prod by TH17), killing of pathogens
Pathology: Neutrophils Lymphocytes Macrophages Granuloma formation
Pathogens:
Klebsiella
Helicobacter
Fungi (candida)
AUTOIMMUNE DISEASES
Chronic inflammation is char predominantly by…
macrophages, lymphocytes, plasma cells
Acute inflammation is char predominantly by…
edema (exudate) and neutrophils (–> macrophages)
Granulomatous
Special type of chronic inflammation
neutrophils can’t digest offending agent, macrophages get stuffed with indigestible substance and form a nodule-granuloma to wall off the offender
The accumulation of macrophages loaded with mycobacteria typically seen in lepromatous leprosy are a likely consequence of:
A defective Th1 response
In chronic inflammation, neutrophils are recruited by a subset of CD4 T cells producing…
IL-17 (TH17 cells)
*neutrophils are also attracted by bacterial products C5a and LTB4
Cell mediated (type IV, CD4 T) Delayed HS rxn Classical, tuberculin type
Typical antigens: Microbial extracts (i.e. tuberculin)
Clinical picture:
Erythema, induration
Histopathology: Cellular infiltrate (lymphocytes, macrophages)
Cell mediated (type IV, CD4, CD8 T)
Delayed HS rxn
Allergic contact dermatitis
Typical antigens:
Urushiol (poison ivy, oak)
Nickel, chromate, leather
Clinical picture:
Blistering, erythema, induration
Histopathology:
Epidermal vesiculation Cellular infiltrate (lymphocytes, macrophages, eos)
Diseases variously based on Th1, Th2 (Ab), Th17 or cytotoxic (CD8) responses, or a combo directed against self antigens…
Lupus erythematosus
Rheumatoid arthritis (*)
Scleroderma
Dermatomyositis
Thyroiditis (Hashimoto’s,
Graves disease)
Type-1 diabetes mellitus (*)
Addison’s disease
Autoimmune gastritis with pernicious anemia
Crohn’s disease and ulcerative colitis (*)
Primary biliary cirrhosis
Multiple sclerosis(*) Myasthenia gravis
Atherosclerosis
Pemphigus Pemphigoid
Vitiligo Alopecia areata
Psoriasis(*) Lichen planus
- TH17 cell driven conditions
The usual chronic inflammatory reaction to non-degradable substances is in the form of foreign body __________ composed of __________ (histiocytes) and ______________________
The usual reaction to non-degradable substances is in the form of foreign body granulomas composed of macrophages (histiocytes) and multinucleated giant cells
*substances are largely non-immunogenic, so do not elicit adaptive immune responses, so lymphocytes/plasma cells are typically rare or absent
Exp. of non-degradable substances causing chronic inflammation
- Exogenous
Mineral: silica (sand, glass), beryllium, zirconium
Plant (thorn), animal (insect parts)
Medical: suture material, synthetic grafts, implants
- Endogenous Calcium, urate crystals, atheroma Storage material Keratin, hair Dead tissue
GRANULOMATOUS INFLAMMATION
- circumscribed collections of inflammatory cells that aggregate around a central “nidus”
- can be composed of macrophages, giant cells, lymphocytes, eosinophils and neutrophils
Classification of granulomatous diseases
Immune (hypersensitivity)-type granulomas
- Caused by microorganisms: i.e. mycobacteria, fungi, spirochetes, parasites
- Unknown cause: i.e. sarcoidosis, Crohn’s disease
Non-immune (foreign body)-type granulomas
- Exogenous materials: i.e. suture material
- Endogenous materials: i.e. crystals, keratin, dead tissue
SCHISTOSOMIASIS (BILHARZIA)
Exp. of a chronic (granulomatous) inflammation
second most important human parasitic disease in the world after malaria
Granuloma mediated by CD4 T cells, Rich in eiosiniphils bc of PARASITES
CHRONIC INFLAMMATION
LONG-LASTING INFLAMMATION IN WHICH AFFECTED TISSUES ARE INFILTRATED MAINLY BY MACROPHAGES, LYMPHOCYES AND PLASMA CELLS
Most cases, EXPRESSION OF AN ADAPTIVE IMMUNE RESPONSE
CAN FOLLOW OR BE ADMIXED WITH ACUTE INFLAMMATION, TISSUE REPAIR AND REGENERATION
APC –> IL-12 –> TH1 –> IFN-gamma
role in chronic inflammation?
killing of intracellular pathogens via activating macrophages
APC –> IL-4 –> TH2 –> IL-4, IL-5, IL-13
role in chronic inflammation?
Killing of extracellular pathogens by stimulating antibody production by B cells
Neutrophils
first on the scene, 4-24 hours and undergo apoptosis in 24-48 hours
Look like messy smiley face, multi-lobed, pink cytoplasmic granules
phagocytose foreign material and kill bacteria
Monocytes
“the clean up crew” arrive after 24 hours (usually day 3), can proliferate, in the tissue –> “macrophages”
Lymphocytes
arrive typically late and are associated with chronic inflammation (*viruses)
huge dark nucleus, little cytoplasm
Plasma cells
late, produce antibodies
Eosinophils
- early responders
- associated with allergic reaction, parasites, drug (Amiodarone), asthma, etc
pink granules
Manifestations of acute inflammation
Purulent (suppurative) - accumulation of pus (dead neutrophils)
Fibrinous (fibrin-rich exudate(proteinRICH). Fibrinogen leaves vessel –> fibrin forms in x-cell space
Serous- fluid accumulation via transudate (protein POOR, few cells)
Acute inflammation sequence
Initiation of inflammation
Increased vascular permeability
Leukocyte extravasation
Acute inflammation initiation
Signal comes from TLR of epithelial and dendritic cells that recognizebacteria and dead cells
Cells secrete cytokines (TNF, IL-1)
Vascular changes of acute inflammation
brief vasoconstriction arteriolar vasodilation (slows blood down, *main vascular change of acute, manifests as erythema/warmth)
Histamine
Key mediator of inflammation
- in mast cells/basophils and platelets
- premade in intracellular granules
pruritus stim vasodilation of arterioles vascular permeability endothelial activation (H1 receptor) hypotension, flushing, headache, tachycardia bronchoconstriction
anaphylaxis/angioedema in sever rxns
Timing of vascular mediators in acute inflammation
Immediate response (15-30 min)
Histamine *
Bradykinin ** PAIN
leukotrienes
Sustained response (4-24 hrs +): Histamine * Bradykinin ** PAIN leukotrienes TNF and IL-1 (cytokines with local and systemic effects)
- –> most imp mediator of inflamma
Increased vascular permeability
Fluid –> extravascular tissues
rbc more concentrated –> inc blood viscosity and a reduction of flow
Transudate vs. exudate
transudate - fluid that passed through the blood vascular wall as a result of hydrodynamic forces.
Low content of cells and protein
Exudate - fluid that escaped from the blood vasculature, usually as a result of inflammation.
High protein and cell content
Expression of selectins regulated by the cytokines
TNF and IL-1
Selectins and their localization
L-selectin on leukocytes
E selectin on endothelium
P selectin on platelets
(p-selectin and von Willebrand factor released from Weibel-Palade bodies granules of endothelial cells due to histamine and thrombin)
rel mediated by TNF, IL-1
TNF-1 and IL-1 –> induce expression of ligands for integrins such as…
VCAM-1 (vascular cell adhesion molecule) the ligand for beta1 integrin (VLA-4)
ICAM-1 (intercellular adhesion molecule) , the ligand for beta2 integrin LFA-1
Mac-1 mediates arrest (the brakes)
Chemokine bind to ____________
endothelial cell proteoglycans
Transmigration
- Margination –> neutrophils accumulation along endothelial surface
- rolling and selectins (E/P/L)
- adhesion and integrins (VCAM, ICAM, MAC –> ligands on endothelial surface, for integrins on leukocyte)
- Transmigration: binding to PECAM-1 (platelet ENDOTHELIAL CELL adhesion molecule)
* piercing basement membrane (collagenase) –> eneters extravascular tissue
Leukocytes normally express integrins in _______ state. VLA-4 and LFA -1 integrins turn into __________ during inflammation.
Leukocytes normally express integrins in low affinity state. VLA-4 and LFA -1 integrins turn into high affinity state during inflammation.
Chemotaxis
- Exogenous (bacterial products)
- Endogenous
Chemokines (IL-8)
Complements (C5a)
arachidonic acid metabolite, leukotriene B4 (LTB4)
Neutrophils and phagocytosis
Neutrophils will phagocytize opsonized (IgG/C3b-bound) bacteria –> phagolysosome
mechanisms of killing…
Myeloperoxidase – reactive oxygen sp.
NADPH oxidase enzyme – free radicals
Vasoactive Mediators (reg/resolution of acute inflammation)
Substances that initiate and regulate inflammatory reactions
- Vasoactive amines (histamine & serotonin)
- Lipid products (prostaglandins and leukotrienes)
- Cytokines/chemokines (TNF,IL-1,IL-8)
- Products of complement activation
Platelets - vasoactive mediator
Histamine, serotonin, & Thromboxane A2.
Cytokines vs chemokine
cytokines –> proteins prod by leukocytes, macrophages, etc, mediate/regulate immune and inflammatory rxns
Exp. TNF, IL-1, IL-6, IL17
chemokines (type of cytokine) –> small proteins acting as chemoattractants for specific leukocytes
Exp. IL-8
TNF
Expression of endothelial adhesion molecule, Secretion of other cytokines
Systemic effect
Prod via Macrophage, Mast cell, T lymphocyte
IL-1
Similar to TNF
FEVER
Prod via macrophages
IL-6
Systemic effect (acute phase response)
Prod via macrophages
Chemokines (IL-8)
Recruitment of leukocytes,
Migration of cells in normal tissue
Prod via macrophages, T-lymphocytes
IL-17
Recruitment of neutrophils and monocytes
Prod by T lymphocyte
Bradykinin
vascular permeability, contraction of smooth muscle, vasodilation and PAIN
(Kallikrein –activator of FXII, chemotaxis, C5 to C5a)
Vasodilation mediator
Histamine
Prostaglandins
Increased vascular permeability mediator
HISTAMINE
Chemotaxis, leukocyte activation
TNF/IL-1
chemokines
FEVER
IL-1
also TNF and prostaglandins
Pain
prostaglandins, brandykinin
Systemic effects in setting of acute inflammation
Fever (via IL1, TNF)
Leukocytosis (IL1, TNF-alpha)
Acute phase reactants (IL6 –> hepatocytes, inc synth of serum proteins)
Sepsis, septic shock, worse
Outcomes of acute inflammation
ulcer - shedding of inflamed necrotic tissue
fistula - abnormal patent connection between two organs
abscess - accumulation of pus walled off with fibrosis
Lab tests to assess inflammation
WBC (leukocytosis) CRP, best ESR (erythrocyte sedimentation rate), worst Lactate dehydrogenase (tissue damage) ALT/AST (cellular damage) Albumin
Acute Phase Reactants
IL-6 acts on liver to make these
CRP
Serum amyloid protein
Slbumin
ESR
Acute inflammation initiation
Signal comes from TLR of epithelial and dendritic cells that recognize bacteria and dead cells
Cells secrete cytokines –> TNF and IL-1
Vascular changes of acute inflammation
brief vasoconstriction
arteriolar vasodilation
APC –> TGF-beta –> T-reg cell –> IL-10, TGF-beta
role in chronic inflammation?
Down-regulation of Th1, Th2, Th17 cells
APC –> IL-23, IL-1, IL-6, TGF-beta –> Th17 cell –> IL-17, CSFs, IL-22, TNF-alpha
role in chronic inflammation?
Killing of extracellular pathogens through recruitment of neutrophils
wbc left shift
IL-1 and TNF mediated leukocytosis
inc in # of immature leukocytes in blood, like neutrophil band cells
Elevated ESR
(Erythrocyte sedimentation rate) if elevated –> inflammatory fx promote RBC rouleaux formation (fibrinogen)
never use this
Elevated CRP
Indic inflammation, can monitor disease state, best marker of inflammation
Decreased albumin
catabolized during inflammation
Plasma cells usually seen in
Chronic inflammation (usually admixed with lymphocytes)
Infection with Syphilis (perivascular plasma cells)
Neoplastic processes (proliferation of clonal plasma cells; multiple myeloma)
*note very blue cytoplasm (where Ig is sitting)
Granuloma formation (usually without necrosis)may be seen in
Fungal infections Infections with parasites Foreign body reactions Sarcoidosis Crohn’s disease Some bacterial infections
Pressures driving fluid out of capillaries, into tissues
- Plasma hydrostatic pressure
- Tissue osmotic pressure
vasodilation –> inc blood flow –> inc hydrostatic pressure –> fluid from capillaries into tissue –> TRANSUDATE
Pressures driving fluid into capillaries
- Tissue hydrostatic pressure
2. Plasma osmotic pressure
Labile cells
continuously divide, usually undergo hyperplasia
exp. epithelia (skin, respiratory urinary, genital mucosa), hemopoietic cells
Stable cells
Normally exhibit slow turnover, but can replicate rapidly in response to gfacs to completely regenerate original tissues
exp. Glandular organs (liver, kidney, pancreas, endocrine glands) Mesenchymal tissues (bone, cartilage, vessels) Glia
Permanent cells
Do not divide. No or limited mitotic activity in post natal life
exp. Skeletal, Cardiac Muscle
Smooth muscle
Neurons
myocardial necrosis –>
brain necrosis –>
myocardial necrosis –> coagulative necrosis
brain necrosis –> liquefactive necrosis
t-PA (tissue plasminogen activator)
thrombolytic med, restores blood flow to blocked coronary arteries
Can cause paradoxical injury (reperfusion injury)
Cardiac muscle enzymes elevated in blood
Creatine Kinase (CK), MB isoform Aspartate transaminase (AST) Lactate dehydrogenase (LDH)
