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Pathobio Exam 1
Set 9: Inflammation & Repair 3, 4, & 5
151
Pathology
Graduate
10/12/2011

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Cards

Term
What are the 2 causes of chronic inflammation?
Definition
1) *persistent tissue injury
2) certain infection types
Term
How does persistent tirrue injury cause chronic inflammation?
Definition
inability to eliminate intial damaging stimulus in a few days => predominance of activated marcophages at site => chemical mediator & oxygen free radical production/release => ongoning tissue damage & cytokines => recruitment of extra monocytes & lymphocytes and growth factors => fibroblast proliferation & development of adaptive immune system => chronic inflammatory cell infiltrate, continuing tissue destruction & fibrosis
Term
What is host defense dependent upon in intracellular pathogens that chronic inflammation?
Definition
cell-mediated immunity
Term
What infiltrate is associated with tissue damage?
Definition
mononuclear inflammatory cell infiltrate ± fibrosis
Term
What are teh components of inflammatory cell infiltrate?
Definition
lymphocytes, marcophages, plasma cells
Term
What does fibrosis associated with tissue damage depend on?
Definition
nature, site, & severity of injury
Term
How do cytokines & GFs increases fibrosis in tissue damage?
Definition
GF => proliferation of fibroblasts & fibrogenic cells => increased collagen synthesis
cytokines => increased collagen synthesis
Term
What are the 2 unique inflammatory responses?
Definition
Granulomatous Inflammaton
Eosinophilic-Predominant Inflammation
Term
def

granulomatous inflammation
Definition
chronic inflammation characterized by distinct aggregates of activated macrophages in addition to the other signs of chronic inflammation (tissue injury & fibrosis)
Term
What 2 agents can cause granulomatous inflammation?
Definition
1) organisms resistant to killing => delayed-type hypersensitivity (i.e. mycobacteria, fungus)
2) particulate matter resistant to degradation => foreign body granulomas
Term
How are granulomas formed?
Definition
persistent stimulation by resistant agents => enlargement, adherence & coalescence of macrophages => activation to T cells => production of IFN-γ & IL-2 (further macrophage activation & augments T-cell response)
Term
What cells form the granuloma?
Definition
clusters of activated macrophages (some may be fused to giant cells) & is frequently surrounded by a rim of lymphocytes
Term
When can central caseous necrosis be within a granuloma?
Definition
if due to infectious causes (esp. TB)
Term
What 2 agents can cause eosinophilic-predominant inflammation?
Definition
1) IgE-mediated type 1 hypersensitivity rxn
2) parasitic inf.
Term
*What is produced by inflammatory cell infiltrate to cause Systemic Inflammatory Response Syndrome (SIRS)?
Definition
cytokines (esp. TNF & IL-1)
Term
*With what type of infections is SIRS most prominent?
Definition
bacterial
Term
*Sx

SIRS
Definition
nonspecific: fatigue, myalgias, & decreased appetite
Term
What causes fever in SIRS?
Definition
COX synthesis stimulation in hypothalamus => prostaglandin formation => increased body temp mediated by various neurotransmitters
Term
def

leukocytosis
Definition
increased WBC
Term
What happens to peripheral WBC count in SIRS?
Definition
usually leukocytosis
Term
*How is WBC count reported?
Definition
in CBC per unit volume, with % of different WBC types
Term
What causes reactive leukocytosis?
Definition
initial increase reserve leukocytes from bone marrow + later increased production of colony stimulating factors => increassed bone marroe leukocyte formation
Term
def

neutrophilia
Definition
increased peripheral neutrophil count
Term
*What causes reactive neutrophilia?
Definition
many types of tissue injury (esp. bacterial inf)
Term
*When is left shift neutrophilia seen?
Definition
significant release of neutrophils from bone marrow
Term
def

left shift neutropehilia
Definition
immature neutrophils seen frequently in the peripheral blood
Term
*What can be stimulated by a marked left shift of neutrophilia?
Definition
leukemia
Term
def

leukemois rxn
Definition
marked left shift of neutrophilia
Term
*What 3 abnormal things can be seen in neutrophils in neutrophilia?
Definition
1) Dohle bodies
2) toxic granulation
3) vacuolization
Term
def

lymphocytosis
Definition
increased peripheral lymphocyte count
Term
What infections tend to produce reactive lymphocytosis?
Definition
viral inf.
Term
def

polyclonal population of lymphocytes
Definition
each clone with unique surface Ag receptors
Term
Besides polyclonal populations of lymphocytes, what other lymphocytes are seen in reactive lymphocytosis?
Definition
atypical lymphocytes (usually activated CD8+ T cells)
Term
def

monocytosis
Definition
increased peripheral monoctye count
Term
When in reactive monocytosis seen?
Definition
chronic inflammatory conditions (s.a. TB)
Term
def

eosinophilia
Definition
increased peripheral eosinophil count
Term
What is reactive eosinophilia often found associated with?
Definition
IgE mediated allergic rxns & parasitic inf.
Term
def

basophilia
Definition
increased peripheral basophil count
Term
When is reactive basophilia seen?
Definition
RARE
Term
What is the acute phase response seen in SIRS caused by inflammation?
Definition
increased or decreased synthesis of APP (mostly by liver)
Term
*What does the acute phase response do to the inflammatory process in the short-term?
Definition
aids in inflammatory process
Term
What does inflammation do to +APP?
Definition
increased plasma concentrations
Term
What 8 +APP are increased in inflammation?
Definition
1) CRP (C reactive protein) 2) SAA (serum amyloid A protein) 3) fibrinogen 4) α1-antitrypsin 5) haptoglobin & ferritin 6) ceruloplasmin 7) factor VIII & von Willeband factor 8) complement proteins
Term
What are the anti-inflammatory cytokines?
Definition
IL-1, IL-6, TNF
Term
What is produced by the liver in response to anti-inflammatory cytokines?
Definition
+APP
Term
What +APP is a fairly sensitive marker of inflammation?
Definition
CRP
Term
Function

CRP
Definition
1)opsonization of damaged cells & some microorganisms
2)activation of complement (via C1 binding - classical)
3)amplification of inflammatory response
Term
When do SAA levels rapidly rise?
Definition
acute inflammation
Term
When can AA amyloidosis form?
Definition
chronic formation of SAA with insufficient degradation
Term
What +APP causes increased erythrocyte sedimentation rate (ESR)?
Definition
fibrinogen
Term
def

ESR
Definition
distance that RBCs settle in a verticle column of anticoagulated blood in 1 hr.
Term
Why test for increased fibrinogen & ESR?
Definition
1) nonspecific marker for inflammation
2) increased risk of thrombosis
Term
Function α1-antitrypsin
Definition
1) inhibit serine proteases
2) anti-inflammatory
=> protection of tissue
Term
Function

haptoglobin & ferritin
Definition
bind free Hb & iron => inability for microorganisms to utilize iron
Term
Function

ceruloplasmin
Definition
scavenges free radicals & facilitates iron binding to ferritin
Term
What does inflammation do to -APP?
Definition
decrease plasma concentrations
Term
What 3 -APP decreased levels => increased availability of substrates & energy for synthesis of +APP?
Definition
1) albumin
2) transferrin
3) retinol-binding protein
Term
Whaat 2 -APP decreased levels lead to temporarily increased bioactive hormone availability?
Definition
1) transthyretin
2) cortisol-binding globulin
Term
Sx

septic shock
Definition
potential multisystem organ failure
Term
What does SIRS lead to septic shock?
Definition
an overwhelming microbial inf.
Term
*What maintains tissue homeostasis?
Definition
closely regulated rates of cellular expansion, differentiation, & apoptosis
Term
What are the 3 classifications of tissues based on proliferative capacity?
Definition
1) labile tissues
2) quiescent (stable) tissues
3) permanent tissues
Term
*What determines what proliferative capacity each organ will have?
Definition
The tisse's proliferative capacity, but most organs have a mixture
Term
def

labile tissue
Definition
cells are continuously being replaced (generally from stem cells)
s.a. hematopoietic cells, mucosal epithelial cells, epidermis
Term
def

quiescent (stable) tissue
Definition
cells are usually resting, but can be stimulated to proliferate
s.a. hepatocytes, fibroblasts, endothelial cells, smooth muscle cells
Term
def

permanent tissue
Definition
cells with very limited regenerative capability
s.a. neurons, cardiac myocytes, skeletal muscle cells
Term
What 2 cells types serve as reservoirs for cellular expansion?
Definition
1) parenchymal cells
2) adult stem cells
Term
*What does the relative contribution of parenchymal cells & adult stem cells in cellular expasion depend on?
Definition
tissue's proliferative capacity & state of health
Term
What is the main cellular replacement source for quiescent tissues?
Definition
parenchymal tissue cells
Term
def

stem cell pools
Definition
capacity for both self-renewal & differentiation
Term
What are adult stem cells the replacement source for?
Definition
labile tissues & injured permanent tissues
Term
What are the 2 types of adult stem cells?
Definition
1) multipotent adult progenitor cells
2) tissue stem cells
Term
What type of adult stem cells are closely related to embryonic stem cells?
Definition
multipotent adult progenitor (due to broad differentiation capacity)
Term
Which tissues have multipotent adult progenitor cells?
Definition
many tissues, including bone marrow
Term
Where are tissue stem cells located?
Definition
outside of the bone marrow
Term
how does tissue stem cells differ from multipotent adult progenitor cells in terms of differentiation capacity?
Definition
tissue stem cells have restricted differentiation capacity
Term
What initiated normal cell replication?
Definition
appropriate stimulus binds receptor => activation od signal transducing proteins => activation of nuclear regulatory proteins => DNA transcription of pre-genes
Term
*What 2 cells (predominately) produce growth factors?
Definition
mesenchymal & inflammatory cells (fibroblasts, activated macrophages, etc)
Term
Function

GFs
Definition
repair in tissue regeneration & healing by fibrosis
Term
*What 6 GFs have a key role in stimulation of replication?
Definition
1) EGF (epidermal)
2) HGF (hepatocyte)
3) VEGF (vascular endothelial)
4) PDGF (platelet derived)
5) FGF (fibroblast)
6) TBF-β (transforming)
Term
Function

EGF
Definition
stimulate proliferation of epithelial cells & fibroblasts
Term
Function

HGF
Definition
promote replication & motility of most epithelial cells
Term
Function

VEGF
Definition
stimulus for growth of new vlood vessels (angiogenesis)
Term
Function

PDGF
Definition
induce migration & replication of fibroblasts, smooth muscle cells & monocytes
Term
Function

FGF
Definition
promotes angiogenesis & influx of multiple cells needed for tissue regeneration
Term
Function

TGF-β
Definition
stimulus for fibrosis & inhibit inflammation
Term
What are the 3 routes of stimulation of repair?
Definition
1) autocrine
2) paracrine
3) endocrine
Term
*What is the most common route of stimulation in tissue regeneration & healing by fibrosis?
Definition
paracrine
Term
def

autocrine
Definition
cell secretes & is the target of stimulus
Term
def

paracrine
Definition
target cell's close to the cell producing signaling molecule
Term
def

endocrine
Definition
secreting sell acts on its target from a distance (usually via the bloodstream)
Term
What 4 receptors are stimulated in cellular proliferation?
Definition
1) *tyrosine kinase receptors
2) w/o tyrosine kinase receptors
3) GPCR (g protein coupled receptors)
4) steroid homone receptors
Term
Which receptor is most frequently utilizaed during tissue repair?
Definition
receptors with intrinsic TK activity
Term
What occurs prior to TK activation after binding of receptor?
Definition
receptor dimerization
Term
What does TK activate in repair?
Definition
mutliple signal transduction pathways
Term
Function

receptors without intrinsic TK activity in tissue repair
Definition
route for cytokine signaling
Term
Function

GPCRs in tissue repair
Definition
diversified rxns activated by multiple ligands
Term
Function

seroid hormone receptors in tissue repair
Definition
transcription factors (localized to nucleus)
Term
def

pro-growth genes
Definition
genes s.a. GFs, GFRs, & proteins promoting cell cycle advancement
Term
*What are the critical cell-cycle regulators?
Definition
cyclins
CDKs
CDK inhibitors
Term
What causes CDK phosphorylation & activation?
Definition
CDK binds to cell-cycle-specific cyclins
Term
What do active CDKs do?
Definition
phosphorylation of key proteins for progression thru the cell cycle
Term
What are the 5 phases of the cell cycle?
Definition
G0 => G1 => S phase => G2 => M phase (=> G0 or G 1)
Term
What occurs in G1?
Definition
synthesis of cyclin D & cyclin E => production of phosphorylated D/CDK & E/CDK => posphorylation of RB protein => trancriptional activation of genes promoting progression thru G1/S check point
Term
What occurs in S phase?
Definition
synthesis of cyclin A => formation of phosphorylated A/CDK
Term
What occurs in G2 phase?
Definition
synthesis of cyclin B => production of phosphorylated B/CDK => initiation of M phase
Term
What is the completion of M phase characterized by?
Definition
removal of phosphate groups from RB protein
Term
What do CDK inhibitors respond to?
Definition
growth suppressing signals
Term
Function CDK inhibitors
Definition
block progression of the cell cycle by inactivating the cyclin/CDK complexes or inhibiting their formation
Term
Where are the 2 cell cycle check points?
Definition
G1/S & G2/M
Term
Function G1/S checkpoint
Definition
check for DNA defects prior to replication
Term
What happens if DNA damage is detected at G1/S checkpoint?
Definition
=> p53 activation => cell-cycle arrect => attempt at DNA repair

if successful: continuation thru cell cycle

if unsuccessful: activation of apoptosis
Term
Function G2/M
Definition
check for DNA defects after replication
Term
what happens if DNA damage is dected at the G2/M checkpoint?
Definition
cell-cycle arrest via p53 dependent & independent processes to allow DNA repair
Term
def

true tissue regeneration
Definition
complete restoration back to the original state
Term
When can true tissue regeneration occur?
Definition
injury to labile & quiescent tissues when ECM framework remains intact
Term
def

compensatory hyperplasia
Definition
restoration of the functional mass, but not the original anatomy
Term
*When might the liver undergo compensatory hyperplasia?
Definition
after partial liver removal
Term
What causes compensatory hyperplasia of the liver?
Definition
paracrine signaling of cytokines & GFs produced by nonparenchymal cells of residual liver => priming & ultimately proliferation of remaining hepatocytes => replication of hepatic nonparenchymal cells
Term
When after tissue injury is there attempt to neutralize the injurous agent & remove the damaged tissue?
Definition
after onset of acute inflammatory response
Term
What type of injury can result in complete tissue restoration?
Definition
mild injury
Term
What type of healing occurs if the injury is sever, persistent or involves permanent cells?
Definition
healing with fibrosis & partial reconstitution of cells capable of regeneration
Term
What are the 2 sequential phases of tissue repair?
Definition
1) granulation tissue
2) scar development
Term
What causes residual inflammation in granulation tissue?
Definition
neutrophils & macrophages still present in an acute injury
Term
*Why is there exudative edema in granulation tissue?
Definition
angiogenesis is occuring, and the immature vessels are leaky
Term
What stimulates angiogenesis in granulation tissue?
Definition
production of VEGF & FGF => migration, proliferation & differentiation of endothelial cells
Term
What causes capillary formation in granulation tissue?
Definition
bone marrow endothelial precursor cells & pre-existing local blood vessels
Term
What causes capillary maturation & stabilization in graulation tissue?
Definition
vessel remodeling, recruitment of surrounding pericytes & smooth muscle cells, and deposition of ECM proteins
Term
What elicits migration & proliferation of fibroblasts in granulation tissue?
Definition
mutiple GFs & inflammatory cytokines supported by extravascular plasma protein framework
Term
What GF is key to all phases of scar formation?
Definition
TGF-β
Term
What are the 3 steps to scar formation?
Definition
1) decrease # of proliferating endothelial cells & fibroblasts
2) increase deposition of ECM
3) CT remodeling
Term
What balances ECM synthesis & degradation in CT remodeling?
Definition
closely regulated matrix metalloproteinases
Term
What are the 5 functions of macrophages in wound healing?
Definition
1) removal of injured tissue/debris
2) antimicrobial activity
3) chemotaxis & proliferation of fibroblasts
4) angiogenesis
5) deposition & remodeling of ECM
Term
What are the 2 patterns of woound healing?
Definition
Healing by first intention
Healing by second intention
Term
What wounds heal by first intention?
Definition
narrow skin wound with minimal tissue damage
Term
What wounds heal by second intention?
Definition
larger skin defect with more extensive tissue damage
Term
Generation of a Fibrin Clot & Acute Inflammatory response

Healing by first intention
Definition
days 1-3: gap filled with a blood clot
influx of neutrophils & then macrophages
beginning epidermal re-epithelialization
Term
Generation of a Fibrin Clot & Acute Inflammatory response

Healing by second intention
Definition
formation of a larger fibrin clot
more extensive tissue destruction w/ a prolonged & more intense acute inflammatory response
Term
Grandulation Tissue Formation & Reconstitution of the Epidermis

Healing by first intention
Definition
days 4-6: residual acute inflammatory cells, esp. macrophages
maximal angiogenesis w/ exudative edema
migration & proliferation of fibroblastsepidermal regeneration
Term
Grandulation Tissue Formation & Reconstitution of the Epidermis

Healing by second intention
Definition
generation and persistence of much larger amounts of granulation tissue; delayed epidermal re-epithelialization
Term
Development of a Scar

Healing by first intention
Definition
over the following several weeks to months
gradual reduction in the number of WBCs, vessels, and fibroblasts
accumulation of collagen
ECM remodeling with increasing tensile wound stength (never completely back to pre-wound strength)
Term
Development of a Scar

Healing by second intention
Definition
more extensive scar formation with significant wound contraction (role of myofibroblasts)
Term
What 5 factors can impede wound healing?
Definition
1) *infection (local or systemic)
2) inadequate circulatory status via decreased blood supply or decreased drainage (impaired venous or lymphatic systems)
3) decreaed immune response
4) malnutrition
5) wound disruption
Term
What are 2 complications of wound healing?
Definition
1) insufficient scar formation
2) excessive scar development
Term
What complications occur due to insifficient scar formation?
Definition
persistent ulceration or wound dehiscence
Term
def

dehiscence
Definition
spontaneous opening
Term
What 4 complication arise in excessive scar development?
Definition
1) overabundant granulation tissue
2) hypertrophic scar
3) keloid
4) contracture
Term
Why is overabundant granulation tissue inhibitory to wound healing?
Definition
prevention of reconstitution of epidermis
Term
def

hypertophic scar
Definition
inordinate accumulation of collagen - results in raised scar
Term
def

keloid
Definition
deposition of extreme quantities of thick, aberrant collagen bands => extensive scar formation
Term
def

contracture
Definition
significant wound contraction => tissue deformaties
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