Ch 1 Inflammation Flashcards
Leukocyte extravasation (4)
1. margination
WBC interacts with endothelial
weak interactions btw glycoprotein adhesion (E,P,L selectins on endothelial) + (integrins on WBC)
2. adherence
WBC to vascular wall high affinity bond
alpha (CD11) + beta (CD18) WBC integrins
**ICAM-1 **adhesions on endothelial
3. diapedesis
WBA migrate inbetween endothelial
via upregulated adhesions molecules on endo (ICAM2)
4. migration
interstitial space along chemical gradient of exogenous or endogenous (chemokines) chemoattractants Il1, TNF substance P
stages of acute inflamm (4)
1. vasodilation
vasoconstriction: stimulted by vasoactive agents (catecholamines, seratonin, bradykinin and PG from tissue
*vasodilation: *new capillaries, inc blood flow and delivery of mediators and cells
NO, histamine, leukotrines, PG, complement
NA fromsympathetic
2. permeability
increased INTRACELLULAR endothelial gaps mediated by histamine and seratonin
inc INTERCELLULAR gaps > hypoxia, injury, cytokines, mediators (TNF, IL-1)
ODEMA loss of serum protien > decreased intravascular osmotic pressure, increased blood viscosity, and subsequent increases in interstitial osmotic pressure
faciliates delivery of factors to site (ab’s, acute phase protien) and pain + loss of function
3. stasis
[inc] RBC + reduced hydrostatic pressure leads to intravascular stasis
INC contact time btw cells and endothelium
4. extravasation
what stimulates initial vasoconsriction (4)
catecholamines,
seratonin,
bradykinin
PG
what stimulates subsequent vasodilation (6)
NO,
histamine,
leukotrines,
PG,
complement
NA from sympathetic
inflammatory cytokines
TNF
IL-1
Permeability involves (3)
- increased intracellular gaps (seratonin, histamine)
- increased intercellular (hypoxia, innjury, cytokines)
3.ODEMA
loss of serum protein
decreased intravascular osmotic pressure,
increased blood viscosity
increases interstitial osmotic pressure
faciliates delivery of factors to site (ab’s, acute phase protien)
pain + loss of function
Celullar components of inflam (4)
1, neutrophils
local killing and degradation of bacterial macromolecules via phagocytosis and superoxide radicals
PRIMARY azurophil granules > microbial peptides and proteases
SECONDARY granules > metalloproteases
prodices:IL-1a, IL1b, IL 6, TNF a
induce relaese - ROS, inflamm
short lived, replaced by macro 24-48hr
2.macrophages
resdient cells source of pro-inflamm factors (IL1b, IL-6, TNFa), PG + growth factors
attracted by: cytokines, compleement, PDGF, TGFb
phagocytose material, pathogens
secrete coallagenases to resolve matrix
stimulate FiBROBLASTS for wound repair
3. lymphocyte
cell mediated immunity: helper (CD4+) T-cells and the cytotoxic (CD8+) T-cells
T-helper-1 (Th-1) and T-helper-2 (Th-2) cells
interferon (IFN)-γ and IL-12, T-cells differentiate + produce cytokines (IFN-γ and IL-2)
Th-1 > **macrophages, maximizing **the bacterial killing
> (IgG) production by B-cells
Th-2 s > allergic reactions
> IL-4, IL-5, IL-10, and IL-13
* suppression of macrophage, increase IgE
4. mast cell
degranulate dt trauma, complement, microbial or neuropeptides
source: histamine, serotonin, leukotrienes, PG, heparin, and cytokines
neutrophils
- job
- granules
- pro-inflamm
1, neutrophils
local killing and degradation of bacterial macromolecules via phagocytosis and superoxide radicals
PRIMARY azurophil granules > microbial peptides and proteases
SECONDARY granules > metalloproteases
produces: IL-1a, IL1b, IL 6, TNF a
induce relaese - ROS, inflamm
short lived
macrophages
- job
- pro-inflamm + GF
- attarcted by
2.macrophages
residient cells, major source of pro-inflamm factors (IL1b, IL-6, TNFa), PG + growth factors
attracted by: cytokines, compleement, PDGF, TGFb
phagocytose material, pathogens
secrete coallagenases to resolve matrix
stimulate FiBROBLASTS for wound repair
lymphocytes
types
stimulated by
produce
cell mediated immunity: helper (CD4+) T-cells and the cytotoxic (CD8+) T-cells
T-helper-1 (Th-1) and T-helper-2 (Th-2) cells
interferon (IFN)-γ and IL-12, T-cells differentiate + produce cytokines (IFN-γ and IL-2)
Th-1 > macrophages, maximizing the bacterial killing
> (IgG) production by B-cells
Th-2 s > allergic reactions
> IL-4, IL-5, IL-10, and IL-13
* suppression of macrophage, increase IgE
mast cells
-produce
degranulate dt trauma, complement, microbial or neuropeptides
source: histamine, serotonin, leukotrienes, PG, heparin, and cytokines
What are inflammatory stimuli (3)
-
ALarm signals
Pathogne associated and danger associated molecular patterns (PAMP + DAMPs)
PAMP: microbial source (foreign)
DAMP: endogenous i.e. fibrinogen, alert damage
group B1 mediator in** late sepsis**
Heat shock protiens - Pattern regcognition receptors
toll-like receptors
intiate intracellular signalling > NF- KB, alter genes -
neurogenic (tachykinins)
neuropeptides released by peripheral nueron + WBC dt trauma
substance P > pain signals + vasodilation (PG, NO) + leukocyte extravasation
substance P (3)
released by: neurons and leukocytes
pain signals (neurokinin reseptors)
vasodilation + oedema via PGs, NO
WBC chemotaxsis/extravasion
inflamm mediators (10)
- vasoactive amines (histamine)
- proinflmmatory cytokines (TNFa, IL1, IL6,
- Chemokines (CXC, CC, IL8, MCP, MIP)
- anitinflamm (IL-10)
- lipid derived (PG, leukotriens, lipoxin)
- platetelt activating factor
- ROS
- NO, HS
- acute phase protiens (albumin, CRP, serum amyloid A, complement)
- coagulation factors
vasoactive amines
Histamine rleased by Mast cells
interacts with H1 recepter
vasodliation
attractes eosionphils
peak affect 15-20min
pro-inflammatory cytokines (4)
-
TNFa
activated macrophages
stimulate pro-infamm cytokines + WBS extravasation
activate T cells -
IL1b
inactive from > cleaved by caspase
enhance pro-inflamm (cytokines, NO, PG) -
IL-6
macrophage, T cell, epithelial
initiate APP
down regulates pro-inflamm
= diagnostic marker -
Chemokines
attract WBC
il-8, monocyte/macrophage chemoarttact protiens
aninflamm
IL 10
produced by CD4+ Th-2 cells, monocytes, B-cells
decrease pro-inflamm + inhbit NFkB
balance the inflammatory response
Eicosanoids (3)
Cell membrane phospholipids»_space;> arachidonic acid via phospholipidase
PG
cyclooxygenase pathway, where arachidonic acid metabolism is catalyzed by the enzymes cyclooxygenase (COX)-1 and COX-2
* COX-1 is a **constitutively **expressed > homeostasis
* COX-2 is **induced **by trauma, growth factors, proinflammatory cytokines
recruitment of leukocytes.
induce vasodilation (pain and fever)
leukotriene
* produced in the lipoxygenase pathway
potent chemotactic agent and an activator of neutrophils
* peptidoleukotrienes provoke vasoconstriction, bronchoconstriction, and increased venule permeability
Lipoxin
major antiinflammatory role (attenuate leukotrienes)
* inhibit neutrophil chemotaxis and transmigration
Platelet activating factor
produced by: enothelial, platelet, WBC
major stimulation of arachidonic acid
subsequently increases eicosanoid production
direct proinflammatory effects on neutrophils
causes aggregation and degranulation of platelets
ROS
Free radicals > destabilize other molecules
ischemia and reperfusion may create ROS
causing peroxidation of membrane phospholipids, which govern cell permeability and the activity of various cellular proteins thus results in oxidative stress and cell damage
induce proinflammatory cytokine (involving NF-κB)
NO, HS
**Nitric oxide **
synthesized from the amino acid L-arginine by the enzyme nitric oxide synthase
(inducible and constitutively produced)
induced by/induces pro inflamm mediators
produces vasodilation
decreases platelet aggregation and leukocyte adhesion
Sustained release occurs in chronic inflammatory joint disorders
Hydrogen sulfide
produced during cysteine metabolism
H2S > promote inflammation
NSAIDs reduce H2S levels > contributes significantly to (NSAID)-associated gastritis
Acute phase protiens (6)
albumin
NEGATIVE APP
C-reative protien
Bound to bacteria, C-reactive protein promotes activation of complement
activated macrophages
DIC
Serum amyoid A
* produced in macrophages and endothelial cells
* stimulates proinflammatory cytokines
chemoaatract t cells
decreases PGe2
Complement
coagulation factors
Kininogen
* plasma proteins of the kallikrein-kinin system Factor XII, prekalli-krein, high-molecular-weight kininogen, and low-molecular-weight kininogen
* bradykinin, inter-acts with two membrane receptors, B1 and B2
complement
hepatically synthesized proteases that circulate in inactive form.
what are 3 pathways
what are 3 actions
activation via 3 pathways:
**Lectin **
interaction lectin proteins with surface carbohydrates on pathogens
**alternative **
contact with foreign microbes
classical pathway
Immune complexes activate
- all complement pathways merge at the cleavage of C3 to form C3b
actions - Inflammation (recruit/activate WBC) C5a, C3b
- phagocytosis C3b
- MAC (C5b binds to C6, C7, C8, and C9 in the terminal complement pathway to form the membrane attack complex
coagulation factors
factors culminate at the conversion of prothrombin, an acute phase protein, to thrombin, which then mediates the conversion of fibrinogen into fibrin and subsequent clot formation
**proinflammatory effects **through four protease-activated receptors (PARs)
- In sepsis and inflammatory conditions complicated by DIC, levels of antithrombin III (ATIII), an inhibitor of thrombin and other coagulation factors, are** reduced**
- activated protein C, limits clotting by inactivating coagulation factors Va and VIIa.
what are the outcomes of inflammation (5)
resolution
- phagocytosis by macrophages
- pro-to-anti-inflamm
systemic inflammation
- multiple factors > intense inflammatory > imbalance of mediators
SIRS: aberrations in temp, heart rate, blood pressure, respiration, and white blood cell counts.
o Dx sepsis = SIRS is accompanied by a nidus of infection
MODs
progressive dysfunction of two or more organ systems
reperfusion-mediated oxidative injury to the gut epithelium serves as a major source of mediators
o “two-hit” phenomenon
Immunosuppession
overwhelming antiinflammatory response
endotoxin tolerance > celll becomes unresponsive to subsequent stimulation.
recent gene analyses suggest that major “reprogramming
chronic inflamm
Chronic inflamm
predominantly monocytic infiltrates, angiogenesis, and progressive tissue fibrosis
o inappropriate expression of proinflammatory factors from stromal cells
o** fibroblasts **play a significant role > promotes expression of pro-inflammatory factors such as IL-6 and COX-2 (vicuous cycle)
Leukocyte-derived growth factors > myofibroblasts and ECM production
granulomatous inflamm > macrophages, epitheloid, multinucleated giant cells (suture and glove startch)
