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
|
|
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
|
|
Term
|
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
|
Definition
|
|
Term
| What happens to peripheral WBC count in SIRS? |
|
Definition
|
|
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
|
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
|
|
Term
|
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
|
Definition
| increased peripheral lymphocyte count |
|
|
Term
| What infections tend to produce reactive lymphocytosis? |
|
Definition
|
|
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
|
Definition
| increased peripheral monoctye count |
|
|
Term
| When in reactive monocytosis seen? |
|
Definition
| chronic inflammatory conditions (s.a. TB) |
|
|
Term
|
Definition
| increased peripheral eosinophil count |
|
|
Term
| What is reactive eosinophilia often found associated with? |
|
Definition
| IgE mediated allergic rxns & parasitic inf. |
|
|
Term
|
Definition
| increased peripheral basophil count |
|
|
Term
| When is reactive basophilia seen? |
|
Definition
|
|
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
|
|
Term
| What is produced by the liver in response to anti-inflammatory cytokines? |
|
Definition
|
|
Term
| What +APP is a fairly sensitive marker of inflammation? |
|
Definition
|
|
Term
|
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
|
|
Term
| When can AA amyloidosis form? |
|
Definition
| chronic formation of SAA with insufficient degradation |
|
|
Term
| What +APP causes increased erythrocyte sedimentation rate (ESR)? |
|
Definition
|
|
Term
|
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
|
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
|
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
|
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
|
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
|
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
|
|
Term
|
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
|
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
|
Definition
| stimulate proliferation of epithelial cells & fibroblasts |
|
|
Term
|
Definition
| promote replication & motility of most epithelial cells |
|
|
Term
|
Definition
| stimulus for growth of new vlood vessels (angiogenesis) |
|
|
Term
|
Definition
| induce migration & replication of fibroblasts, smooth muscle cells & monocytes |
|
|
Term
|
Definition
| promotes angiogenesis & influx of multiple cells needed for tissue regeneration |
|
|
Term
|
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
|
|
Term
|
Definition
| cell secretes & is the target of stimulus |
|
|
Term
|
Definition
| target cell's close to the cell producing signaling molecule |
|
|
Term
|
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
|
|
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
|
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
|
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
|
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
|
Definition
| synthesis of cyclin A => formation of phosphorylated A/CDK |
|
|
Term
|
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
|
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
|
|
Term
|
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
|
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
|
|
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
|
|
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
|
Definition
|
|
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
|
Definition
| inordinate accumulation of collagen - results in raised scar |
|
|
Term
|
Definition
| deposition of extreme quantities of thick, aberrant collagen bands => extensive scar formation |
|
|
Term
|
Definition
| significant wound contraction => tissue deformaties |
|
|
