Exam 1 Flashcards
(156 cards)
1
Q
Anatomic pathology
A
Based on gross, microscopic, chemical, immunologic and molecular examination of organs, tissues and cells.
2
Q
clinical Pathology
A
Based on the laboratory analysis of tissue and fluid (blood, urine, body cavities).
3
Q
Four aspects of disease
A
–Etiology (cause)
–Pathogenesis (mechanism)
–Morphological changes (structural)
–Clinical-pathological effects (clinical manifestations)
4
Q
Disease Etiology
A
Genetic
- Inherited mutations
- Disease-associated gene variants
Acquired
- Infectious
- Nutritional
- Chemical
- Physical
5
Q
DISEASE
A
A cluster of signs, symptoms and laboratory findings linked by a common patho-physiologic sequence.
underlying pathology
Most epidemiology is about disease.
6
Q
ILLNESS
A
The subjective state of the individual who feels aware of not being well.
The ill individual may or may not be suffering from disease.
social/culteral conceptions of condition
7
Q
SICKNESS
A
The social role assumed by an individual suffering from an illness.
what pt birngs to doc
8
Q
natural history of disease
A
progression of a disease process in an individual, over time, in the absence of treatment
course a disease takes in individual people from its pathological onset (“inception”) until its eventual resolution through complete recovery or death
9
Q
CELLULAR HOMEOSTASIS
A
The steady state in which cells normally exist
The equilibrium of the cells within their own environment (Adequate function preserved)
An increase, decrease, or change in stress on an organ can result in growth adaptations
When disturbed, there is a predisposal for the onset of pathology (Function may be lost)
10
Q
cellular adaptations: REVERSIBLE
A
increased demand, trophic stim (horm, GF)
- Hyperplasia: Increase in number of cells
- Hypertrophy: increase in size of cell and then organ
Decreased nutrients, stimulation
- Atrophy: decrease in size, but no loss of function
- Hypoplasia: decrease in the number of cells
chronic irritation:
- Metaplasia: One adult cell type is replaced by another
Dysplasia:
- Abnormal growth with
- loss of cellular orientation/shape/size
- NOT truly adaptive
11
Q
CELLULAR ADAPTATIONS: irreversible
A
anaplasia:
- loss in structural differentation & fx
- “primitive”
- may see “giant cells”
neoplasia:
- uncontrolled/excessive/irreversible prolif of cells
- abnorm fx –> death
desmoplasia:
- fibrous tissue formation in response to neoplasm
12
Q
Neoplastic progression (4)
A
- Hyperplasia/dysplasia
- Carcinoma/preinvasion
- neoplastic cells have not yet invaded basement membrane
- Large nuclei with high amount of chromatin
- Invasive carcinoma
* Basement membrane is invaded via collegenases and hydrolases (metaloproteases) - Metastisis-
* “seed and soil”: carcinomic embolus spreads and invades another organ
13
Q
HYPERTROPHY
A
increase cell size –> increased organ size
- Greater synthesis of structural components
- In cells with limited capacity to multiply
causes:
- increased fx demand
- GF stim
- horm stim
types:
- physio: increased demand/stimuli
- increased work load –> increased M fiber size
- patho: chronic hemodynamic overload
- hypertension/valve deficiency –> injury/death (MI)
14
Q
MECHANISMS OF HYPERTROPHY
A
cause:
- mechanical: increased work/stretch
- GF (trophic): TGF-β, IGF-1, FGF
- vasoactive agents: Noradrenaline, dopamine, adrenaline
signal txduction pathways –> increase protein synth
Ts fac: GATA4, NFAT, MEF2
triggers:
- induction emb/fetal genes: cardiac alpha-actin, ANF
- more E saving contraction: α isoform of myosin heavy chain is replaced by β isoform
- synth contractile proteins
- production of GF
result:
- increase mechanical performance
- decrease work load
“Point of no return” vs lesion
15
Q
A
16
Q
Limits of Hypertrophy
A
- vasc
- biosynth machineary
- cell injury on persistence of stress
17
Q
HYPERPLASIA
A
Cellular proliferation stimulated by growth factors
- important for wound healing
physiological
- horm
- compensatory: residual tissue grouth after removal/partial loss of organ
patho
- excess horm stim/GF
- chronic irritation
- stim antibodies
- viral infection
18
Q
ENDOMETRIAL HYPERPLASIA
A
STIMULUS FROM THE HYPOPHYSE HORMONES AND ESTROGEN FROM THE OVARIES
19
Q
“BPH”
A
STIMULATED BY ANDROGENS
reversible when no mutations and initial stimulus is removed
assosciated with aging
20
Q
breast development
A
physio hyperplasia
prolif gladular epithelium: puberty/preg
21
Q
compensatory hyperplasia
A
INDIVIDUALS WHO DONATE A A PART OF THE LIVER HAVE IT RESTORED TO ITS ORIGINAL SIZE
22
Q
A
23
Q
patho hyperplasia: chronic irritation
A
Bronchial mucous gland hyperplasia in smokers & asthmatics
Thickening of skin following constant scratching
Regenerative nodules in cirrhotic liver due to alcohol
24
Q
Graves disease
A
thyroid enlargement due to thyroid stimulating auto-antibodies
mimics TSH
goiter: visibly enlarged thyroid
25
HPV
epidermal hyperplasia: wart
26
MECHANISM OF HYPERPLASIA
- Only noted in cells which have the ability to divide
- Increased local production of GF
- Activation of particular intracellular signaling pathways
- Leads to production of transcription factors
- no stimulus = stops = Remains controlled = “Point of no return”
- If continuous = risk of malignancy
27
HYPERTROPHY OR HYPERPLASIA?
Dividing (Labile) cells
* Stem cells --\> hyperplasia
Non dividing (Permanent) cells
* skeletal/cardiac muscle cells --\> hypertrophy
Stable cells
* Hepatocytes, smooth muscle cells --\> hyperplasia/ hypertrophy on stimulation
28
ATROPHY
Shrinkage in the size of the cell by loss of cell substance
Adaptive response
Function is diminished but not lost
29
physio atrophy
embryogensis:
* notochord
* thyroglossal duct
involution:
* mamm glad after lactation
* ovary after menopause
* uterus after birth
30
PATHOLOGIC ATROPHY
1. defcreased workload: prolong immob of limb
2. loss of innervation: skeletal M atrophy
3. loss of endocrine stim: hypopitutiary, menopause
4. diminished blood supply: heart/brain in atherosclerosis
5. inadequate nutrition: marasmus
6. intraluminal P: CF thick secretions --\> panc atrophy
7. brain: age + reduced blood flow
31
MECHANISMS OF ATROPHY
- Combination of decreased protein synthesis (reduced gene expression and reduced metabolism) and increased protein degradation
- Decreased metabolism of cell organelles
- Degradation of cellular proteins (Stimulation of ‘ubiquitin-proteasome’ pathway)
- Stem cells are intact
**often accompanied with increased autophagy**
32
DEVELOPMENTAL CAUSES OF REDUCED CELL MASS
•Agenesis
–Complete lack of formation of an organ
•Aplasia
–Remnant of the organ exists
•Hypoplasia
–Incomplete growth of the organ
–Failure to reach the normal size
33
METAPLASIA
one adult cell replaced with another --\> better able to withstand adverse enviroment
reversible if irritant removed but predisposed to malignancy
causes:
* often secondary to irritation/enviroment exposure (inflamm/irritation)
* reprog stem cells
common types:
* epithelial, mesenchymal
34
EPITHELIAL METAPLASIA
Chronic smokers
* Columnar to squamous epithelium
* Squamous metaplasia of bronchial mucosal lining
Barrett’s esophagus
* Squamous to columnar epithelium:
* Distal end of esophagus
35
MESENCHYMAL METAPLASIA
Osseous
* New bone formation in injured muscle or tendon or cartilage
Myeloid
* Extra medullary hematopoiesis
36
MECHANISMS OF METAPLASIA
- Reprogramming of stem cells (vs. trans differentiation)
- Differentiation of stem cells along a particular lineage
- Brought about by various cytokines, growth factors
37
DYSPLASIA
disordered cell growth/maturation: loss of size/shape/orientation
often accompanied by hyperplasia/metaplasia = atypical hyperplasia
reversible in **theory**: if stress alleviated - short duration
prolife of pre-ca cells: long duration --\> ca
causes:
* chronic irritation/inflam
* accumulation genetic mutations
38
difference between hysplasia and neoplasia
**no invasion of basal lamina**
can progress to ca
* stress persistance:
* cerv intraepithelia neoplasia (CIN): dysplasia --\> precursor to cerv-ca
* metaplasia --\> dysplasia --\> ca
* long term patho hyperplasia: endometrial hyperplasia --\> displasia --\> ca
39
risk factors of dysplasia
* Infection – HPV 16, 18 --\> Cervical dysplasia
* Chemicals – Smoking
* Ultraviolet light - squamous dysplasia of skin
* Chronic irritation – skin in third degree burn --\> squamous dysplasia
* Some types of hyperplasia (e.g endometrial hyperplasia)
* Some types metaplasia (e.g. Barrett’s Esophagus)
40
MORPHOLOGY OF DISPLASIA
nuclear:
* larger
* hyperchromasia: more basophilic
growth changes
* increase mitosis
* disorderly prolif
poor maturation
* abnorm architecture/arrangement
41
metaplasia --\> dysplasia --\> neoplasia
42
Mechanisms of accumulation
1. inadeq removal of norma lsubstance:
* prob with packing/txp
* fatty liver
2. accumulation abnormal endogenous substance:
* genetic/acquired defect in folding/packing/txp
* Mutated forms of α1-antitrypsin
3. failure to degradea metabolite
* inherited enz defic
* storage disorders
4. accumulation abnormal exogenous substance
* lack of enz/txp
* carbon, silica
43
TYPES OF INTRACELLULAR ACCUMULATIONS
44
STEATOSIS
fatty change: accumulation TAG in parenchymal cells
* abnormal fat metab
* REVERSIBLE
common in:
* liver
* heart
* skel M
* kid
morphology:
* organ enlarges --\> yellow discoloration
45
ETIOLOGY OF STEATOSIS
1. obesity
* NASH: fat & inflam/scarring
2. alcohol
* alters metabolism:
* NADH --\> accumulate DHAP --\> G3P --\> TAG
* acetyl CoA --\> FA
* decreased beta-ox
3. protein malnutrition
* Kwashiorkor
* decreased apolipoprotein to coat VLDL
4. drugs: tetracycline, amiodarone
5. anoxia: CO poisoning
6. Reye's syndrome
46
Accumulation of lipid in phagocytic cells: common presentations
atherosclerosis
* macrophage/smooth M cells: intimal layer of bv
xanthoma
* macrophages in subepithelial connective tissues/tendons
cholesterolosis
* macrophages in lamina propria of gallbladder
niemann-pick: type C
* mutation in cholesterol txp enz
47
protein accumulation examples
nephrotic syndrome: PCT
russel bodies: plasma cells
alcoholic (mallory) hyaline: liver
neurofbrillary tangles: neurons in Alzheimers
amyloid: amyloidosis
48
Nephrotic syndrome
protein leakage --\> increadsed reabsorption --\> pink hyaline cytoplamstic droplets (pinocytic vesicles fusing with lysosomes)
reversible if droplets metab & disappears
49
Russell bodies: excessive production
## Footnote
immunoglobulin in plasma cells --\> accumulation in RER --\> round/eosin bodies
50
Amyloidosis: aggregation of abnormal proteins
## Footnote
* Stained with Congo red
* Shows apple green birefringence when polarized
51
Mallory bodies or "alcoholic hyalin" - accumulation of cytoskeletal proteins
* Eosinophilic
Liver
* Mallory bodies
* alcoholic liver disease
Aggregated intermediate filaments that resist degradation
52
* Alzheimer disease
* Aggregated protein inclusion that contains microtubule-associated proteins and neurofilaments
53
Glycogen accumulation
normally stored in cytoplasm
deposits: clear vacuoles (carmine, PAS stains)
diseases:
* DM: renal tubular epithelium, islets of Langerhan, myocardial cells
* glycogen storage disorders: liver, skel M
54
exogenous pigments
–Carbon – Anthracosis
–Tattoos
–Lead – in renal tubular cells in lead poisoning
55
endogenous pigment
–Lipofuscin
–Melanin
–Hemosiderin
–Bilirubin
56
Anthracosis (coal dust)
* Phago by alveolar macrophages (Dust cells) and transported through lymphatic channels to tracheobronchial lymph nodes
* Coal workers pneumoconiosis
57
Morphology: Perinuclear, intra-lysosomal electron dense granules
yellow brown
wear & tear pigment
mechanism: peroxidation of lipids by free radicals
common in heart/liver
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59
MELANIN
* Brown-black pigment produced by melanocytes (epidermis)
* Accumulates in keratinocytes & macrophages à hyperpigmentation
* Nevus (mole/birthmark)
* Malignant melanoma
* Increased ACTH
* Addison’s disease
* Pituitary adenoma
* Adrenogenital syndrome
60
Golden brown granules – breakdown of ferritin
* stored in lysosomes & not found in serum (ferritin found in serum)
Prussian blue staining
61
examples that produces hemosiderin
iron overload
* hemosiderosis: in macrophages - not associated with dysfx
* hemochromatosis: parenchymal cells (aquired/hereditary)
* bronze diabetes
* cirrhosis
* CHF
stasis dermatitis
DVT
sideroblastic anemia
anemia of chronic disease
62
- Cholestatic liver
- Basal ganglia in kernicterus
63
Pathological Calcification
abnorm deposits of CaPO4
1. dystrophic:
* dead/dying tissues
* absense of deranement in Ca2+ metab
* normal serum calcium
2. metastatic:
* normal tissues
* abnorm in Ca2+ metabolism
* hypercalcemia
64
DYSTROPHIC CALCIFICATION pathogensis steps
* Initiation --\> Propagation
* Intracellular – initiated in the mitochondria of dying cells
* Extracellular – membrane bound vesicles from the dying cells --\> calcium concentrated due to the affinity for membrane phospholipids --\> phophate accumulates due to phophatase
* Propagation --\> depends on the degree of collagenization & the presence of mineral inhibitors
65
DYSTROPHIC CALCIFICATION examples
–Atherosclerotic plaques
–Damaged heart valves
–Chronic pancreatitis
–Psammoma bodies in meningioma & papillary carcinoma of thyroid
–Periventricular calcification in cytomegalovirus infection
66
METASTASTIC CALCIFICATION
* Calcium deposits in the interstitium of blood vessels, kidneys, lungs, gastric mucosa
* May cause dysfunction if extensively calcified
* Nephrocalcinosis
* Respiratory insufficiency
67
METASTASTIC CALCIFICATION causes
hypercalcemia
* hyperPTH
* bone destruction: Paget's, immobilization, malignancy
* vit-d intox
* sarcoidosis
* renal failure --\> secondary hyperPTH
hyperphosphatemia
68
Morphology of calcification
69
Necrosis
* Damage to cell membranes
* Loss of ion homeostasis
* •Lysosomal enzymes
* •Cell digestion
* •Leak through plasma membrane
* •Host reaction (inflammation)
•Pathway of cell death in injuries from:
* •Ischemia
* •Toxin exposure
* •Various infections
* •Trauma
*
70
Apoptosis
cell suicide: dna/prot dmged beyond repair
* nuc dissoln
* frag without complete loss of memb integrity
* rapid removal cell debris
no leaking! --\> no inflamm
high reg
not necc assoc with cell injury
71
necrosis v apoptosis
72
reversible cell injury
gen swell, PM blebbing, ribo detachment, clump nuc chromatin
associations:
* dec ATP
* loss cell memb integrity
* def in prot synth
* cytoskel dmg
* DNA dmg
73
irreversible injury/cell death
necrosis
* mito dmg
* deplete ATP
* rupture lyso, PM
are...
* ischemia
* toxis
* infections
* trauma
74
cell swelling
cannot maint ion/fl homeo --\> fail E-dep ion pumps in PM
reversible
75
fatty change
hyposix, toxic, metab injury
lipid vac in cytop (cells dep on fat metab)
* hepato
* myocardial
76
morph features of necrosis
denat intra-cell prot --\> enz dig of ijured cell
features:
* inc eosinophilia
* nuc
* karyolysis
* pyknosis
* karyorrhexis
77
•Coagulative necrosis
archit preserved
ischemia: bv obstruct
local = infarct
78
•Liquefactive necrosis
dig dead cells --\> liquid mass --\> creamy yellow pus
focal bac/fungal infections
involves CNS
79
•Gangrenous necrosis
usu limb, gen lower
gang + liquifactive necrosis = wet gangrene
80
caseous necrosis
cheese-like
granulomas: TB
81
fat necrosis
fat destruc
usu acute pancreatitis
82
fibrinoid necrosis
immune rxn with bv
antigen-antibody complexes
83
A 33-year-old woman has increasing lethargy and decreased urine output for the past week. Laboratory studies show serum creatinine level of 4.3 mg/dL and urea nitrogen level of 40 mg/dL. A renal biopsy is performed and the specimen is examined using electron microscopy. Which of the following morphologic changes most likely suggests a diagnosis of acute tubular necrosis?
A.Mitochondrial swelling
B.Plasma membrane blebs
C.Chromatin clumping
D.Nuclear fragmentation
E.Ribosomal disaggregation
A.Nuclear fragmentation
84
A 63-year-old man has a 2-year history of worsening congestive heart failure. An echocardiogram shows mitral stenosis with left atrial dilation. A thrombus is present in the left atrium. One month later, he experiences left flank pain and notes hematuria. Laboratory testing shows elevated serum AST. Which of the following patterns of tissue injury is most likely to be present?
A.Liquefactive necrosis
B.Caseous necrosis
C.Coagulative necrosis
D.Fat necrosis
E.Gangrenous necrosis
A.Coagulative necrosis
85
•Cell response to injurious stimuli depends on the
* Nature of the injury
* Duration
* Severity
86
•Consequences of cell injury dependent on the injured cell’s
* Type
* State
* Adaptability
87
cell injury: depletion of ATP
fund cause of necrotic cell death: hypoxia, toxic
major causes:
* decreased o2, nut
* mito dmg
* tox
atp effect only at 5-10% norm lvls
* PM sodium pump
* change in cell metab
* fail Ca2+ pump
* reduced protein synth
* unfolded protein response
irreverible dmg to mito/lyso memb --\> necrosis
88
mito dmg
dmg by:
* increased cytosolic calcium
* ROS
* o2 depriv
conseq:
* mito perm txition pore
* ROS
* leak prot --\> cytosol --\> apoptosis
89
calcium
increased intracell ca2+ --\> cell inj
in mito: opens mito perm txition pore --\> ATP gen fail
in cytosol: activ enz: phospholipase, protease, endonuc, ATPase
apoptosis
* direct activ of caspases
* increase mito perm
90
Oxidative Stress
ROS gen
* metab
* radient E
* inflam
* exogen chem/drugs
* txision metals
* NO
ROS removal:
* antiox
* bindnign free Fe2+/Cu2+
* catalase, SOD, glu-perox
91
Pathologic Effects of Free Radicals
lipid perox in memb
ox mod of prot
DNA changes: aging, malig txform
92
memb permea mechanism
ROS
dec ppl synth
inc ppl brkdown
cytoskel abnorm
93
conseq of memb dmg
mito: dec ATP/prot prod
plasma: loss osm bal --\> influx fl/ions, leakage contents/metabolities
lyso: enz leak
94
Damage to DNA and Proteins
DNA: drugs, radiation, ox stress
improp folded proteins: mut, triggers (ROS)
95
always irreversible injury
inab to reverse mito dysfx
profound disturbance sin memb fx
96
tissue specific cell injury
cardiac: CK isoform, troponin
liver: alka (P)ase isoform
hepatocytes: txaminases
irreversible: inc lvls proteins in blood
97
ischemic injuries
hypoxic
* reduced blood flow (mec A obstruction) --\> persis --\> irreverislble --\> necrosis
reperfusion
* restore of blood flow exacerbates injury
* ox
* intracell Ca2+ overload
* inflam
* activ of complement
98
chem (toxic) injury
direct:
* mercury Cl
* CN
* antineoplastic chemo
* antibiotics
coversion to toxic metabolities:
* cytP450
* ROS
* lipid perox
* carbon tetraCl
* tylenol
99
A 55-year-old man complains of a sudden onset of chest pain 3 hours ago. Laboratory studies show an increased cardiac troponin level. He is given tissue plasminogen activator (t-PA). His troponin level following the therapy is increased further. Which of the following best explains the increase in the troponin level?
A)Increased generation of reactive oxygen species
B)Glycogen depletion
C)Loss of Na+ and water
D)Increased oxidase activity
E)Calcium influx
A)Increased generation of reactive oxygen species
100
caspase
cys proteases that cleave prot after aspartic residues
mech of apoptosis
101
intrinsic pathway of apoptosis
mito: major
inc permea --\> release death-inducing mol (by BCL2)
* anti: BCL2, BCL-X, MCL1
* pro: BAX, BAK
* sensors: BAD, BIM, BID, Puma, Noxa
102
extrinsic pathway of apoptosis
init by PM death receptors on cells --\> deliver apop sig
103
final phases of apop
2 pathways converge --\> caspase activation
cytop DNAse cleaves DNA
caspase degrad nuc matrix
apop bodies phagoed:
* sol fac
* thrombospondin
* natural antibodies/prot: C1q
104
Necroptosis
hybrid of necrosis and apop
resembles necrosis morph:
* loss ATP
* swell cell/org-lls
* ROS
* release lyso enz
* rupture PM
resembles apop mech:
* sig txduction trigger
* **does not involve caspase activation**
105
necroptosis pathway
occurs during growth plate form
106
necroptosis assoc with cell death in.... (5)
steatohepatitis
acute pancreatitis
reperfusion injury
parkinsons
cytomegalovirus
107
pyroptosis
release cytokine IL-1
108
autophagy
cell eats own contents: chaperone-med, micro, macro
steps:
* forms iso memb (phagophore) & nucleation
* elong vesicle
* matur --\> fusion with lyso
dysreg in...
* ca
* neurodegen disorders
* inflam bowel dis
109
cell aging
prog decline in fx & viability
* gen abnorm
* accum cell/mol dmg due to exposure
mech:
* DNA dmg
* senescence: telomere attrition, activ tumor suppressor genes
* defective protein homeostatis
* dereg nut sensing
110
inflamm
protective response to infection/inj
brings defense cells/mol
elim init cause & necrotic cells/tiss
init process of repain
111
typical inflam rxn steps
5 R's
recog
recruit: leukocytes, plasma prot
removal
reg: rxn controlled/term
resolution/repair
112
inflam: recognition
init by innate immune sys: macrophages, dendritic, mast, etc...
PRR (pattern recog receptors) recog PAMPS/DAMPS (pathogen/dmg-assoc mol patterns) --\> host cell releases inflam mediations
113
examples of PRRs
toll-like receptors:
* bac prod: endotoxin, bac DNA
* virus prod: dbl-standed DNA
inflammasone:
* multiprot cytop complex: recog prod of dead cells
* extracel ATP
* induce prod IL-1 (inflam cytokine)
114
major particip in inflam rxn =
bv:
* dilate/dev perma to leuko/plasma
leukocytes:
* recruitment
115
inflammation: resolution/repair
elim of inflam:
* mediators brkdwn/dissipated
* leuko = short life span
* anti-inflam mech activated: lipoxins, TGFβ, IL-10
regen surv cells
fill residual defects with conn tiss (scarring)
116
harmful conseq of inflam
protection may injure "bystander" tissues
* infections diff to eradicate: TB
rxn misdirected: autoimmune/allergy
chronic inflam
* atherosclerosis
* DM 2
* alzheimers
* ca
117
5 cardinal manifestations of inflammation
redness (rubor) : bv dil/inc blood flow
heat (calor): bd dil/inc blood flow
swell (tumor): accum fl/inflam cells
pain (dolor): stretch/distortion tiss by inflam fl, pain-inducing inflam mediators
loss of fx: swell/pain inhib mvmt
118
inflam: changes in vasc
txsient vasoconstrict --\> A vasodil --\> inc blood flow & permea --\> loss fl to extravasc tissue (inflam edema - "exudate") --\> increased [RBC] --\> stasis (inc visc/slow of blood flow) --\> margination leukocytes (displace to periphery of bv) --\> emigation of leuko thru vessel wall
119
transudate
extravasc fl : secondary to osm/hydrostatic inbal
* low prot content (mostly albumin)
* little/no cell mat
* low sp grav
120
Exudate
extravasc fl: secondary to inc permea bv due to inflam
* high protein content
* high cell debris
* high sp grav
121
Pus or purulent exudate
Exudate rich in leukocytes (mostly neutrophils), debris of dead cells, and often microbes
122
Increased vascular permeability:
Mechanisms
•Contraction of endothelial cells resulting increased interendothelial spaces
•
•Endothelial injury, necrosis, and detachment
•
•Transcytosis - increased transport of fluids and proteins
•
•Leakage from immature new blood vessels (angiogenesis)
•
123
inflam: lymph
increaese lymph flow to drain excess fl/leuko/cell debris/microbes --\> 2ndary inflam
lymph-angitis/adenitis
124
Leukocyte recruitment steps
* Margination and rolling along the endothelial surface
* Stable adhesion to the endothelium
* Transmigration between endothelial cells
* Migration in interstitial tissues toward a chemotactic stimulus
125
Margination and rolling
in stasis, leuko pushed to perip of lumen
endothelial cells active cytokines which express selectin adhesion mol --\> weakly bind to leuko --\> roll (txient bind/detach to endothelial surf)
126
stable adhesion of leuko
integrins on leuko cell surf: ICAM-1, VCAM-1
* cytokines inc affinity
127
diapedesis
driven by chemokines prod by extravasc tiss
PECAM-1/CD31: adhesion mol on leuko & endothelium --\> homotypic binding
collagenases: leuko mol --\> pass thru BM
128
chemotaxis of leuko
chem [] gradient:
* bac prod
* chemokines
* complement (C5b)
* leukotriene B4
pseudopods --\> anchor to ECM --\> cytoskel pulling
* directed by higher density chemokines on leading edge
129
inflam: types of cells recruited
most acute: neutrophils first 6-4 hrs --\> replaced by macophages in 24-48 hrs
* neutrophils = shortlived --\> apop after 24 hrs
* macophages = can surv for months
viral: lymophocytes = 1st to arrive
hypersens rxn: eosinophils = mai cell type
130
phago steps
recog/attachement
engulf with phago vacuole
kill/degrad ingested material
* lyso: ROS, NO - phagolysosome
131
Reactive oxygen and nitrogen species
H₂0₂-MPO-Halide system
* phago --\> ox burst
* NADPH oxidase --\> superoxide & H202
* --\> MPO
* H2o2 + Cl --\> HOCl (bacteriocidal)
N-derived free radicals:
* NO --\> peroxynitrite
132
o2-indep microbial killing
lysozyme: degra bac coat oligosacc
major basic protein: eosinophil - parasites
defensins: peptides that create holes in microbe memb
133
elastase
leuko enz
dig dead tissues
134
•Neutrophil extracellular traps (NETs)
extracell fiber netwks rod by neutrophils in response to patho/inflam mediators
nuc chromatin embedded with antimic peptides/enz
* nuc cromatin may be source of nuc natigens in autoimmue dis (lupus)
135
IL-17
prod by T lymphocytes (Th17 cells)
adaptive immunity
recruit neutrophils/monocytes: acute inflam
136
Principal mediators of inflammation
•Cell-derived
–Vasoactive amines
–Cytokines (including chemokines)
–Arachidonic acid metabolites
–Platelet activating factor
•Plasma protein-derived
–Complement
–Kinins
137
Histamine
from mast cells (mainly), also basophils, platelets
stim:
* phy injury
* IgE: allergy
* complement binding: C3a, C5a
dil arterioes, inc permea venules
* bind to H1 receptors
* H1 receptors antagonists (antihistamine) = tx allergies
138
Serotonin
vasoactive amine
in platelet granules --\> aggreg
139
Arachidonic acid
20-C polyunsat FA: norm esterified as cmpt of memb ppl
inflam --\> release AA from meb ppl via PPL A
* cyclooxygenase: PG, Tx
* lipoxygenase: HETES, leukotrienes lipoxins
140
AA metabolites
PG: local vasodil/permea, pain/fever during inflam
LT: local chemotaxis/ brochospams, vasc permea
lipoxins: inhib inflam
141
Platelet activating factor
ppl-derived mediator
aggreg platelets & inflam effects
142
Cytokines and chemokines
med/reg immune/inflam rxns
chemokines: chemoattractant cytokines acting on leukocytes
143
cytokines of acute inflam
TNF: expr endothemlial adhesions mol, secr other cytokines, sys effects
IL-1: sil to TNF - greater role in fever
IL-6: acute sys effects
chemokines: recruit leuko to inflam
IL-17: recruit neutrophils, monocytes
144
cytokines of chronic inflam
IL-12: incr prod IFN-gamma
IRN-gamma: activ macro: incr ab to kill microbes/tumor cells
IL-17: recruit neutrophils monocytes
145
Complement System
plasma prot: circ as inactive --\> activ via amplying cascade (C1-C9)
**crit step**: C3 activation via 3 pathways: classic, alt, lectin
146
Major biologic activities of complement
•Inflammation
–C3a and C5a (anaphylatoxins) stimulate release of histamine from mast cells
–C5a is chemoattractant
•Opsonization
–C3b fixed to microbial wall acts as opsonin promoting phagocytosis
•Cell lysis
–Deposition of the pore-forming membrane attack complex (MAC), resulting in cell lysis
147
kinins
precursos high MW kininogen (HMWK) --(kallikrein)--\> bradykinin
effects: sim to histamine
* dil bv
* inc vasc permea
* contract smooth M
* pain
anaphylaxis
148
Factor XII
149
Morphologic hallmarks of acute inflammation
150
Morphologic hallmarks of acute Inflammation
* Serous inflammation
* Fibrinous inflammation
* Purulent (suppurative) inflammation
* Abcess
* Ulcer
151
serous inflam: skin blister
152
Fibrinous inflammation:
Fibrinous pericarditis
153
Purulent inflammation:
Lung abscesses
154
Purulent inflammation:
Pneumonia
155
Ulceration:
Duodenal ulcer
156
Outcomes of acute inflammation
