inflamation and phagocytosis Flashcards
the __ and ____ events that highlight ____ inflammation serve to deliver mediators of host defense (_____ and _______) to sites of microbial invasion and or tissue injury
vascular cellular acute leukocytes plasma proteins
inflamation
the reaction o vascularized living tissues to local injury
inflammation is
- an evoke response set in motion by some kind of stimulus; occurs only in living things
- fairly stereotypical regardless of the inducing stimulus
- an overlapping series of events that form a continuum
the inflammation response may have three out comes:
- elimination of the causative agent
- walling off of the inflammation from the rest of the body with subsequent healing of the lesion
- persistence of the causative agent, leading to chronic inflammation or spread throughout the body
although inflammation is characteized by the controlled passage of cells, ____ and _________ into the injured tissue, sometimes it can be ___ _____ than the initiating stimulus
plasma
plasma components
more harmful
rubor
caused by increased blood flow, dilation of arterioles and vascular perfusion of the area
tumor
caused by diapedesis of blood cells and plasma from the post capillary venules into the damaged tissue
calor
local increase in tissue temperature
dolor
caused by stimulation of neuronal pathways by bradykinin, histamine, serotonin, and prostaglandin
functio laesa
loss of function
the local inflammatory response is ____ accompanied by ____ changes collectively called the ____ phase response or _____ ____ response syndrome.
always
systemic
acute
systemic inflammatory
these systemic responses to infection are due to the actions of _____ ____ such as ___________, ________, and _______ secreted by activated macrophages, mast cells, etc.
proinflamatory cytokines
tumor necrosis factor
interleukin-1
interleukin-6
other cytokines that also participate in the acute phase response include ____ ____ ___ that stimulat the bone marrow to produce more white blood cells
colony stimulating factor
the acute phase response includes the following:
- fever
- leukocytosis
- increased synthesis of acute phase proteins
- decrease in the plasma concentration of iron.
- decrease in appetite
- increased secretion of many hormones, notably ACTH and cortisol
T or F
low concentration of free iron enhances bacterial replication
F
-High
acute phase proteins
are plasma proteins whose concentrations change by at least 25% during inflamation
what is a negative acute phase protein?
albumin
acute phase proteins are synthesized mostly by the
liver
acute phase proteins play various rolls in the innate immune system, they include:
- complement proteins
- C-reactive protein
- mannose-binding protein
- iron binding proteins
- lipopolysaccharide-binding protein
C-reactive protein
has the ability to bind to the C-protein of pneumococci.
-binds to bacteria and promotes their uptake by phagocytic cells a process referred to as opsonization.
opsonization
the uptake of bacteria by a phagocytic cell
mannose-binding protein
binds to mannose residues on the surface of a bacterial cell, resulting in its opsonization
what is an example of an iron binding protein
haptoglobin
lipopolysaccharide- binding protein
enhances the ability of macrophages and other cells to detect and respond to Gram-negative bacteria
microvasculature consist of:
afferent arterioles, the capillary networks, and the efferent venules
following tissue injury, initation of the inflammatory response occurs at the level of the ____ and _____ ____ venules
capillary
postcapillary
arterioles
the initial response is transient vasoconstriction, mediated by neurogenic and chemical stimuli. then vasodilation occurs with increased blood flow to the inflamed area
capillaries
the reaction of endothelial cells in the capillaries to vasoactive mediators leads to EC retraction, gap formation, and increased permeability
post capillary venules
primary anatomic site for inflammation- related leakage
T or F
endothelial cells are less sensitive to vasoactive mediators
F
more sensative
chemical mediators
are chemical messengers that
enhance blood flow,
increase vascular permeability, or
induce the emigration of leukocytes from the blood stream to the
site of tissue injury.
exogenous sources of chemical mediators:
bacterial LPS
endogenous chemical mediators originate from both ___ and ____
plasma
host cells
cellular sources of chemical mediators include
- platelets
- connective tissue mast cells
- basophils
- neutrophils
- endothelial cells
- fibroblast
- monocyte/ tissue macrophages
- injured tissue
vasoactive mediators include:
- histamine
- serotonin
- bradykinin
- nitric oxide
- leukotriene
- prostaglandins
- platelet -activating factor
- anaphylatoxins
- LPS
- cytokines
chemotactic factors
- C5a
- leukotriene
- formylated peptides
- chemokines
- PAF
vasoactive mediators cause
vasodilation
increased vascular permeability
endothelial expression of adhesion molecules
chemotactic factors cause
recruitment and stimulation of inflammatory cells
T or F
most functions can be elicited by multiple mediators and most mediators serve multiple functions.
T
Many mediators exert their effects ____ and do not circulate systemically in ___ concentration.
locally
high concentrations
LPS
released from the cell wall of Gram-negative bacteria is recognized and bound to LPS binding protein present in plasma
macrophage activation happens when:
LBP enhances the transfer and presentation of LPS to the CD14 receptor on macrophage cell membrane
the activated macrophage synthesizes and secretes vasoactive mediators of inflammation including:
IL-1 IL-6 CXCL-8 TNF- alpha PAF
nitric oxide
- important mediator of inflammation
- causes vasodilation by relaxing vascular smooth muscle
- reduces platelet aggregation and adhesion
- is a potent microbicidal agent
nitric oxide is produced by
activated endothelial cells and
activated macrophages
leukocyte recruitment begins with
dilation of post capillary venules
what are the steps that follow dilation of postcapillary venules
- leukocyte rolling
- activation
- margination/pavementing
- transendothelial migration
subsequent movement through the extracellular matrix to the site of inflammation or tissue injury occurs under the influence of
chemotactic factors
the 4 major families of adhesion molecules are:
selectins
addressins
integrins
immunoglobulin superfamily
selectins
adhesion molecules expressed on platelets, leukocytes, and endothelial cells that promote the initial localization and rolling of leukocytes along endothelium at sites of tissue injury
each selectin molecule is a _____ chain transmembrane_____ with an extracellular lectin domain
single
glycoprotein
P-selectin
is preformed and is stored within Weibel-palade bodies of ECs and the alpha-granules of platelets.
Pselectin binds to an _____ on ___, ______, and ______ cell surfaces call P-selectin glycoprotein ligand-1
addressin
neutrophil,
monocyte
T-lymphocyte
E selectin
is synthesized and expressed by endothelial cells within 1-2 hours after proinflamatory cytokine activation
e selcting binds to e-selectin ligand-1 on the surface of
granuloytes, monocytes, and t lymphocytes
L-selectin
is expressed on lymphocytes, granulocytes, monocytes, and macrophages
L-selectin binds to
CD34
glycan-bearing cell adhesion molecule-1
mucosal addressin cell adhesion molecule-1
Vascular addressins
mucin-like molecules that possess carbohydrate regions that bind the lectin domain of selectins
addressins are expressed on the surfaces of
leukocytes and endothelial cells
T or F
selectin-addressin binding is a strong bond
F- they are not a strong bond
integrins
- are transmembrane adhesive proteins expressed on leukocytes
- composed on alpha and beta subunits, arranged as heterodimers
- several subfamilies that express a conserved beta chain
major functions of integrins are to
mediated adhesion of leukocytes to endothelial cells, extracellular matrix proteins, and adhesion of T cells to antigen presenting cells or target cells
T or F
some integrins bind to proteins that participate in the inflamatory response.
T
integrins are always present on the surface of leukocytes but are quicly up-regulated in numbers and adhesiveness following activation of leukocytes by
chemoattractants
the up-regulated sticky integrins on activated leukocytes then bind to their counterreceptors on ECs, resulting in the stable adhesion of leukocytes to the endothelium, this is also know as:
pavementing
the significance of integrin proteins in leukocyte extravasation is demonstrated by ______ ______ _______ disease, which is characterized by recurrent bacterial infections.
leukocyte adhesion deficiency
immunoglobulin superfamily
a family of proteins that share partial amino acid sequence homology and tertiary structural features that were originally identified in immunoglobulin heavy and light chains
some members of the family are expressed on the cell surface of cytokine- stimulated ______ cells and _____ and help localize leukocytes to areas of tissue damage.
endothelial cells
leukocytes
ICAM-1 (CD54)
expressed by proinflam. cytokine activated ECs. it is also expressed by a variety of cells including B lymphocytes and monocytes/macrophages
ICAM-1 counter receptor is
CD11aCD18
I CAM-2 (CD102)
constitutively expressed at low levels on some ECs. also expressed by monocytes/macrophages and some Tcells.
VCAM-1(CD 106)
expressed by activated ECs. also expressed by macrophages and other cells
VCAM-1 counter receptor is
VLA-4
Platelet endothelial cell adhesion molecule (PECAM-1)
present on neutrophils, platlets, monocytes, B cells;
PECAM-1 is also found where
junctional complex of activated ECs
Homotypic binding
PECAM-1 molecule on one cell binds to PECAM-1 molecule on another cell
Diapedesis
enhanced by binding of PECAM-1 on neutrophils to its twin PECAM-1, expressed on ECs close to the inter-endothelial cell junction
this is an exit sign for neutrophils
in most bacterial infections, ______ predominate during the first ________ hours of the inflammatory reaction.
neutrophils
6-24
in most species, other than ___and ___, neutrophils are the most numerous WBCs in circulation
pigs and cattle
T or F
Neutrophils respond more slowly to chemotactic agents.
False
more rapidly
In the later stage( 24-48 hours) of the inflammatory reaction, ____ and ____ predominate.
monocytes
lymphocytes
in immediate hypersensativity reactions and parasitic infestations _____ predominate
eosinophils
chemotaxis
the energy-dependent, unidirectional migration of cells toward increasing concentrations of a soluble chemotactic agent
a receptor mediated event
chemokinesis
random, excited movement of cells
haptotaxis
chemotactic agents bind to extracellular matrix protein, thereby creating a fixed chemotactic gradient
leukocyte chemoattractants can be divided into two basic types
classical leukocyte attractants
chemokines
classical leukocyte attractants
act broadly on several cell types, including monocytes, macrophages, and neutrophils
classical leukocyte attractants include:
bacterial chemotaxins dead cells plasma derived: C5a/C3a/C5b67 platelet activating factor Leukotriene B4
chemokines
they are the most important group of chemotactic agents
include:
CXC chemokines
CC chemokines
CXC chemokines
potent attractants and activators of NEUTROPHILS
most significant is CXCL8 (IL-8)
CC chemokines
they attract various leukocytes but not neutrophils
phagocytosis
process by which certain cells of the innate immune system, including macrophages and neutrophils engulf large particles, such as bacteria, fungi, protozoa
Elie Metchnikoff
credited for discovering phagocytosis
he also concluded that inflammation served as an important defense reaction of the body and played a major part in bringing about recovery from bacterial infections
polymorphonuclear neutrophils (PNMs)
make up 40-70% of the total blood leukocyte population in most animal species except in pigs in cattle
what are the predominate peripheral blood cells in pigs and cattle
lymphocytes
Majority of PMNs are stored in the _____ and are released when ________ mediators reach the bone marrow via the blood stream, and there, act on the marrow capillaries and on stored PMNs to mobilize them into the circulating blood.
bonemarrow
proinflammatory
once released from bone marrow _____ do not have the ability to divide and give rise to new cells.
neutrophils
T or F
an adult human produces over 1X10^11 neutrophils ever week.
F
its supposed to be per day
Neutrophils circulate in the blood for about ___ to ___ hours and then migrate into tissues where they may survive for up to ___ to ___days
4 to 8
4 to 5
if a PMN is not recruited into a site of inflammation what happens to it
undergoes programmed cell death and is usually phagocytosed by resident macrophages in the liver or spleen
the neutrophils of ____, ___, and ________ contain large reddish staining cytoplasmic granules, hence they are refereed to as ____.
chickens
rabbits
guinea pigs
heterophils
attachment between the neutrophil and the microbe is mediated by the interaction between __ ____ _____ and _____ on the microbe
cell surface receptors and ligands
_____ and ____ recognize conserved microbial structures that are relatively invariant with a pathogen class. these structures are termed______________(____) eg, LPS, lipoteichoic acid, peptidoglycan, mannose-rich ogliosaccharides, etc. the receptors on phagocytes that recognize them are called____________.
neutrophils and macrophages
pathogen-associated molecular patterns (PAMPS)
pattern recognition receptors (PRRs)
opsonins
are naturally occurring(nonspecific) or acquired (specific) substances that coat microbes and render them more susceptible to phagocytosis
Opsonons, being ____ charged proteins help to neutralize the ___ charges on foreign particles, enabling them to bind to negatively charged phagocytes
positively
negative
Specific opsonin
IgG
fab portions bind to epitopes on the microbe
Fc portion binds to Fcgamma receptor on phagocyte
nonspecific opsonins
complement proteins C3b, iC3b, C4b and a number of plasma proteins including fibronectin, manose-binding lectin (MBL) and C-reactive protein
Nonspecific opsonization is ___ effective than IgG coating but can enhance _____ early in the course of infection before specific antibodies are produced.
less
phagocytosis
following attachment, the adherent particle stimulates ____ formation of the cell membrane.
pseudopodia
phagosome
phagocytic vesicle that is free floating now do to breaking away from the cell membrane
following engulfment lysosomal granules migrate through the cytoplasm and fuse with phagosome to form____, where microbicidal molecules and the proteolytic enzymes stored in lysosomes come into contact with and destroy the phgocytized microbe
phagolysosome
microbial killing occurs with in
10-30min
primary granules
defensins
myelo-peroxidase
neutral and acid hydrolases
lysozyme
defensins
disrupt plasma membrane
myelo-peroxidase
respiratory burst
natural and acid hydrolases
degrade bacterial products
lysozyme
destroys bacterial cells walls
secondary granules
lysozyme
lactoferrin
collagenase
lactoferrin
binds iron
collagenase
degrades connective tissue
respiratory -burst is characterized by
two-three fold increases in O2 consumption by the cell, (b) increased glucose oxidation via the hexose monophosphate shunt, and (c) generation of microbicidal reactive oxygen intermediates: superoxide anion, hydrogen peroxide, hypochlorous acid, hydroxyl radical, and singlet oxygen
_____ is the most potent microbicidal system in neutrophils
H2O2-myeloperoxidase-halide system
oxygen independent killing
lysozyme
defensins
bactericidal permeability increasing protein
lysozyme
a mucopeptidase found in serum, sweat, tears, saliva, mucus, nasal secretions, phagocytes and tissue fluids
what breaks down bacterial cell wall peptidoglycan by hydrolyzing the glycosidic bond between the monosaccharides of the peptidoglycan backbone, there by rendering the bacterium susceptible to osmotic lysis
lysozyme
lysozymes are effective against whome
gram-positive bacteria
defensins
a group of small peptides found in phagocytes and certain intestinal cells.
form ion-permeable channels in microbial cell membrane, resulting in escape of essential metabolites
can kill or inactivate a wide variety of bacteria, fungi, and some enveloped viruses
bactericidal permeability increasing protein
binds specifically to the outer membrane of gram negative bacteria
BPI induces
- phospholipase activation
- phospholipid degranulation
- increased permeability in the outer membrane of the bacterium
neutral and acid hydrolases
degrade and digest killed bacteria within the phagolysosome
Neutrophils lack ____ , thus they possess a limited supply of energy reserves which cannot be replinished
mitochondria
following phagocytosis, neutrophils rapidly undergo ___ cell death and are ingested by macrophages
apoptotic
The MMS consists of _____, _________, and ____ or ____ ____ ____
monocytes
macrophages
resident or fixed tissue macrophages
upon release from bone marrow, monocytes circulate in the blood for __ to ___ hours before migrating into tissues, where they undergo maturation to become tissue macrophages.
10-20 hrs
resident of fixed tissue macrophages and macrophage -like cells
serve as the first line of phagocytic defense when microorganisms breach the physical barriers
alveolar macrophages are found
in the lungs
pulmonary intravascular macrophages are found in
ruminants, cats, and pigs
in the capillaries of the lungs
Free macrophages
derived from blood monocytes constitute the majority of macrophages at inflammatory sites. a small portion may come from fixed macrophages which can undergo cell division when appropriately stimulated
macrophages play a roll in both ____ and ___ immunity and are important effector cells for the elimination of microorganisms.
innate and adaptive
macrophages can live for ___ to ___ unless they are destroyed by performing functions
months to years
Unlike neutrophils, macrophage lysosomes also contain large amounts of _____, which digest the thick lipid membranes possessed by some bacteria.
lipases
Macrophage membrane receptors consist of
cytokine receptors
complement receptors
antibody receptors
integrins
__________ receptors on cell membrane bind to mannose or fucose residues in the capsule of LPS f invading bacteria, allowing macrophages to bind directly to ________ bacteria
Mannose-binding
nonopsonized
Macrophages respond to the same chemoattractants that neutrophils do along with:
CC chemokines
cationic peptides released by dead and dying neutrophils
lymphokines released by activated T cells( migration inhibition factor and macrophage chemotactic factor)
unlike neutrophils, macrophages are
sluggishly motile
macrophages can engul
rbc
neutrophils
necrotic debris
compared to neutrophils, a macrophage is capable of phagocytizing as many as ___ bacteria
100
activated macrophages can synthesize ___, a vey powerful microbicidal agent
nitric oxide
in chronic inflammation, macrophage accumulation will persist; this is mediated by multiple mechanisms:
- recruitment of monocytes from circulation
- macrophage proliferation
- immoblization of macrophages
when stimulated, macrophage may increase in size and form clusters of _____ or several may fuse to form_____
epithelioid cells
multinucleated giant cells
macrophages play a major roll in:
tissue reorganization and wound healing
Macrophage proteinases
degrade connective tissue; the cellular debris is then phagosytized. they also synthesize and secrete many growth factors that promote the proliferation of fibroblasts and the growth of new blood vessels
what are the many functions of macrophages
-antigen presentation
-tissue reorganization and wound healing
-secretion
cytokines
enzymes
other factors
-tumor cell destruction
-phagocytosis and destruction of bacteria
when neutrophils and macrophages engage in phagocytosis, they can injure normal host tissues by release of
ROI and lysosomal enzymes
antoproteinases
- synthesized by the liver, leukocytes, and connective tissue
- present in plasam and tissues (alpha-2 maroglobulin and alpha-1antitrypsin), inhibit leukocyte proteinases, there by preventing and/or minimizing tissue damage
escape of reactive oxygen metabolites
cytocolic and plasma molecular “scavengers” of oxyradicals limit damage to cells and tissues
catalase and glutathione peroxidase, both present in cells, convert escaped H2O2 to H2O and O2
cytotoxicity
membranolytic substances such as bacterial leukocidin, urate crystals, can damage the membrane o the phagolysosome, spilling out potent hydrolytic enzyme
kills leukocyte and released into tissues
regurgitation during feeding
large numbers of bacteria= increased feeding and results in the fusion of the lysosome with the developing phagosome, prior to complete closure
lytic enzymes in lysosome have direct access to the extracellular environment
frustrated phagocytosis
phagocyte encounters phagocytic stimuli that are too large to be internalized (parasites, bacteria, antigen-antbody immune complexes on basement membrane)
undere these conditions release of lysosomal enzymes by the phagocyte into the surrounding environment occur leading to tissue injury- vasculitis
