Acute Inflammation
Inflammation: response of vascularized tissue that delivers leukocytes and molecules of host defense from the circulation to the sites of and cell damage in order to eliminate the offending agents
Onset | Sudden |
---|---|
Duration | Short (minutes to days) |
Cellular Infiltrate | Mainly neutrophils |
Tissue Damage | Minimal |
Acute Disorders | Cells and Molecules Involved in Injury |
---|---|
Acute respiratory distress syndrome | Neutrophils |
Asthma | Eosinophils; IgE antibodies |
Glomerulonephritis | Antibodies and complement; neutrophils, monocytes |
Septic shock | Cytokines |
Polymorphneuclear leukocytes (PNL) or neutrophils:
migrate from the blood
Function: phagocytosis
characteristic cells of acute inflammation
Pus cells (dead polymorph nuclear leukocytes)
release lysosomal enzymes which liquefy necrotic tissues, forming pus
Vascular dilation leading to an increase in blood flow
Increased permeability of the microvasculature allowing plasma proteins and leukocytes to leave the circulation
Emigration of leukocytes from blood vessels, their accumulation in the focus of injury and activation to eliminate the offending agent
Edema: excess fluid in interstitial tissue or body cavities.
Can either be:
Exudate: inflammatory extravascular fluid with cellular debris and high protein concentration
presence reflects increased vascular permeability
Transudate: excess extravascular fluid with low protein content
an ultrafiltrate of blood plasma resulting from elevated fluid pressures or diminished plasma osmotic forces
Pus: purulent inflammatory exudate rich in neutrophils and cell debris
Begins immediately after injury
Vasodilation: increases flow into areas of injury = increasing hydrostatic pressure
Increased vascular permeability causes exudation of protein-rich fluid
Vasodilation + fluid loss = increased blood viscosity and increased concentration of red blood cells = stasis
with stasis, leukocytes (mostly neutrophils) accumulate along endothelium (marginate) and are activated by mediators to increase adhesion and migration through vessel wall
Increased vascular permeability can be induced by:
Contraction of venule endothelium to form intercellular gaps
most common mechanism
evoked by chemical mediators (histamine, bradykinin, leukotrienes (LTs))
occurs rapidly
Direct endothelial injury
severe necrotizing injury (e.g. burns) causes endothelial cell necrosis and detachment that affects blood vessels
recruited neutrophils may contribute to injury (e.g. through reactive oxygen species)
immediate and sustained endothelial leakage
Increased transcytosis
transendothelial channels form by:
interconnection of vesicles derived from the vesiculo-vacuolar organelles (VVO)
Vascular endothelial growth factor (VEGF) and other factors
represent a secondary line of defense
in inflammation, lymphatic flow is increased to drain edema fluid, leukocytes, and cell debris from extravascular space
in severe injuries, drainage may also transport the offending agent
lymphatics may becomes inflamed
lymphangitis
manifest grossly as red streaks
draining lymph nodes may becomes inflamed
lymphadenitis
manifest as enlarged, painful nodes
usually due to lymphoid follicle and sinusoidal phagocyte hyperplasia (reactive lymphadenitis)
recognize invading pathogens and necrotic debris, eliminate them, and produce growth factors to facilitate repair
type of leukocyte depends on the original stimulus and duration of inflammatory response
Bacterial infections: neutrophils
Viral infections: lymphocytes
Allergic reactions: increased eosinophils
Hypersensitivity reactions: mixed
Necrosis: neutrophils (6 to 24 hours), replaced by monocytes (24 to 48 hours)
Leukocyte movement:
Margination and rolling
Adhesion and transmigration
Chemotaxis and activation
Phagocytosis and degranulation
In normally flowing blood in venules red blood cells are confined to a central axial column
as blood flow slows (stasis), leukocytes accumulate at the periphery of vessels along the endothelial surface
tumbling of leukocytes on the endothelial surface, transiently sticking along
Mediated by: selectin molecules
3 types:
L-selectin: expressed on leukocytes
E-selectin: expressed on endothelium
P-selectin: expressed on platelets and endotheium
bind via lectin domains to oligosaccharides on cell-surface glycoproteins
regulated by cytokines produced in response to infection and injury
P-selectin activated by: histamine and thrombin
E-selectin activated by: IL-1 and tumor necrosis factor (TNF)
Endothelial cells | Leukocytes |
---|---|
E-selectin | Sialyl-Lewis X-modified glycoproteins |
P-selectin | Sialyl-Lewis X-modified glycoproteins |
Sugar moieties of glycoproteins | L-selectin |
Mechanism of Rolling
leukocytes express L-selectins at the tips of their microvilli and also express ligands for E-selectin and P-selectin, all of which bind to the complementary molecules on the endothelial cells
low affinity interactions with a fast off-rate
easily disrupted by flowing blood
leukocytes bind, detach and bind again
roll along the endothelial surface
firm adhesion of leukocyte to endothelial cell surface
mediated by:
integrins on leukocytes
immunoglobulin superfamily on endothelial cells: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1)
immunoglobulin molecules on endothelial cells that bind integrins on leukocytes
lymphocyte function associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1) bind ICAM-1
very late antigen-4 (VLA-4) binds to VCAM-1
Chemoattractants (chemokines) and cytokines affect adhesion and transmigration
after histamine exposure, P-selectin is rapidly translocated to the cell surface
TNF and IL-1 induce endothelial expression of E-selectin, ICAM-1, and VCAM-1
integrins are converted from low-affinity to high-affinity forms by chemokines
Transmigration (diapedesis): crawling of leukocytes between endothelial cells and squeezing along the intercellular junctions and through basement membrane into extracellular space
occurs mainly in postcapillary venules
mediated by: homotypic interactions of platelet endothelial cell adhesion molecules (PECAM-1 or CD 31)
cell-cell adhesion molecule of immunoglobulin superfamily
secrete collagenase and degrade basement membrane
after leukocytes pass through the basement membranes become continuous again
migrate toward chemotactic gradient
Chemotaxis: movement of leukocytes towards the site of inflammation
coordinate by chemotactic factors (chemotaxins)
Chemotactic factors: certain chemical substances and certain bacterial products that are able to attract leukocytes towards the site of inflammation
Include:
Endogenous factors
complement system components (C5a)
Arachidonic acid metabolites (leukotriene B4 (LTB4))
cytokines, especially chemokines (interleukin-8 (IL-8))
Exogenous factors
soluble bacterial products
Activation of leukocytes through:
chemotactic factors
degranulation and secretion of lysosomal enzymes
generation of oxidative burst
arachidonic acid metabolites production (LTB4)
modulation of leukocyte adhesion molecules
Phagocytosis (to eat and destroy): engulfment of foreign materials by phagocytic cells
Two major phagocytes:
neutrophils
macrophages
Phagocytosis involves:
Recognition and attachment of a particle
Engulfment
Killing and degradation of the ingested material
Killing and degradation mechanisms:
oxygen-dependent mechanisms (oxidative burst)
inside phagolysosome
production of free oxygen radicals
uses: NADPH oxidase, MPO in azurophilic granules
oxygen-independent mechanisms
leukocyte granules contains substance capable of damaging and killing bacteria:
bactericidal permeability increasing protein
lysosomal enzyme, able to liquefy necrotic materials
major basic protein
defensins
Fever
Leukocytosis
C-reactive protein positive
Cloudy swelling of parenchymatous organs
Inflammation: response of vascularized tissue that delivers leukocytes and molecules of host defense from the circulation to the sites of and cell damage in order to eliminate the offending agents
Onset | Sudden |
---|---|
Duration | Short (minutes to days) |
Cellular Infiltrate | Mainly neutrophils |
Tissue Damage | Minimal |
Acute Disorders | Cells and Molecules Involved in Injury |
---|---|
Acute respiratory distress syndrome | Neutrophils |
Asthma | Eosinophils; IgE antibodies |
Glomerulonephritis | Antibodies and complement; neutrophils, monocytes |
Septic shock | Cytokines |
Polymorphneuclear leukocytes (PNL) or neutrophils:
migrate from the blood
Function: phagocytosis
characteristic cells of acute inflammation
Pus cells (dead polymorph nuclear leukocytes)
release lysosomal enzymes which liquefy necrotic tissues, forming pus
Vascular dilation leading to an increase in blood flow
Increased permeability of the microvasculature allowing plasma proteins and leukocytes to leave the circulation
Emigration of leukocytes from blood vessels, their accumulation in the focus of injury and activation to eliminate the offending agent
Edema: excess fluid in interstitial tissue or body cavities.
Can either be:
Exudate: inflammatory extravascular fluid with cellular debris and high protein concentration
presence reflects increased vascular permeability
Transudate: excess extravascular fluid with low protein content
an ultrafiltrate of blood plasma resulting from elevated fluid pressures or diminished plasma osmotic forces
Pus: purulent inflammatory exudate rich in neutrophils and cell debris
Begins immediately after injury
Vasodilation: increases flow into areas of injury = increasing hydrostatic pressure
Increased vascular permeability causes exudation of protein-rich fluid
Vasodilation + fluid loss = increased blood viscosity and increased concentration of red blood cells = stasis
with stasis, leukocytes (mostly neutrophils) accumulate along endothelium (marginate) and are activated by mediators to increase adhesion and migration through vessel wall
Increased vascular permeability can be induced by:
Contraction of venule endothelium to form intercellular gaps
most common mechanism
evoked by chemical mediators (histamine, bradykinin, leukotrienes (LTs))
occurs rapidly
Direct endothelial injury
severe necrotizing injury (e.g. burns) causes endothelial cell necrosis and detachment that affects blood vessels
recruited neutrophils may contribute to injury (e.g. through reactive oxygen species)
immediate and sustained endothelial leakage
Increased transcytosis
transendothelial channels form by:
interconnection of vesicles derived from the vesiculo-vacuolar organelles (VVO)
Vascular endothelial growth factor (VEGF) and other factors
represent a secondary line of defense
in inflammation, lymphatic flow is increased to drain edema fluid, leukocytes, and cell debris from extravascular space
in severe injuries, drainage may also transport the offending agent
lymphatics may becomes inflamed
lymphangitis
manifest grossly as red streaks
draining lymph nodes may becomes inflamed
lymphadenitis
manifest as enlarged, painful nodes
usually due to lymphoid follicle and sinusoidal phagocyte hyperplasia (reactive lymphadenitis)
recognize invading pathogens and necrotic debris, eliminate them, and produce growth factors to facilitate repair
type of leukocyte depends on the original stimulus and duration of inflammatory response
Bacterial infections: neutrophils
Viral infections: lymphocytes
Allergic reactions: increased eosinophils
Hypersensitivity reactions: mixed
Necrosis: neutrophils (6 to 24 hours), replaced by monocytes (24 to 48 hours)
Leukocyte movement:
Margination and rolling
Adhesion and transmigration
Chemotaxis and activation
Phagocytosis and degranulation
In normally flowing blood in venules red blood cells are confined to a central axial column
as blood flow slows (stasis), leukocytes accumulate at the periphery of vessels along the endothelial surface
tumbling of leukocytes on the endothelial surface, transiently sticking along
Mediated by: selectin molecules
3 types:
L-selectin: expressed on leukocytes
E-selectin: expressed on endothelium
P-selectin: expressed on platelets and endotheium
bind via lectin domains to oligosaccharides on cell-surface glycoproteins
regulated by cytokines produced in response to infection and injury
P-selectin activated by: histamine and thrombin
E-selectin activated by: IL-1 and tumor necrosis factor (TNF)
Endothelial cells | Leukocytes |
---|---|
E-selectin | Sialyl-Lewis X-modified glycoproteins |
P-selectin | Sialyl-Lewis X-modified glycoproteins |
Sugar moieties of glycoproteins | L-selectin |
Mechanism of Rolling
leukocytes express L-selectins at the tips of their microvilli and also express ligands for E-selectin and P-selectin, all of which bind to the complementary molecules on the endothelial cells
low affinity interactions with a fast off-rate
easily disrupted by flowing blood
leukocytes bind, detach and bind again
roll along the endothelial surface
firm adhesion of leukocyte to endothelial cell surface
mediated by:
integrins on leukocytes
immunoglobulin superfamily on endothelial cells: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1)
immunoglobulin molecules on endothelial cells that bind integrins on leukocytes
lymphocyte function associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1) bind ICAM-1
very late antigen-4 (VLA-4) binds to VCAM-1
Chemoattractants (chemokines) and cytokines affect adhesion and transmigration
after histamine exposure, P-selectin is rapidly translocated to the cell surface
TNF and IL-1 induce endothelial expression of E-selectin, ICAM-1, and VCAM-1
integrins are converted from low-affinity to high-affinity forms by chemokines
Transmigration (diapedesis): crawling of leukocytes between endothelial cells and squeezing along the intercellular junctions and through basement membrane into extracellular space
occurs mainly in postcapillary venules
mediated by: homotypic interactions of platelet endothelial cell adhesion molecules (PECAM-1 or CD 31)
cell-cell adhesion molecule of immunoglobulin superfamily
secrete collagenase and degrade basement membrane
after leukocytes pass through the basement membranes become continuous again
migrate toward chemotactic gradient
Chemotaxis: movement of leukocytes towards the site of inflammation
coordinate by chemotactic factors (chemotaxins)
Chemotactic factors: certain chemical substances and certain bacterial products that are able to attract leukocytes towards the site of inflammation
Include:
Endogenous factors
complement system components (C5a)
Arachidonic acid metabolites (leukotriene B4 (LTB4))
cytokines, especially chemokines (interleukin-8 (IL-8))
Exogenous factors
soluble bacterial products
Activation of leukocytes through:
chemotactic factors
degranulation and secretion of lysosomal enzymes
generation of oxidative burst
arachidonic acid metabolites production (LTB4)
modulation of leukocyte adhesion molecules
Phagocytosis (to eat and destroy): engulfment of foreign materials by phagocytic cells
Two major phagocytes:
neutrophils
macrophages
Phagocytosis involves:
Recognition and attachment of a particle
Engulfment
Killing and degradation of the ingested material
Killing and degradation mechanisms:
oxygen-dependent mechanisms (oxidative burst)
inside phagolysosome
production of free oxygen radicals
uses: NADPH oxidase, MPO in azurophilic granules
oxygen-independent mechanisms
leukocyte granules contains substance capable of damaging and killing bacteria:
bactericidal permeability increasing protein
lysosomal enzyme, able to liquefy necrotic materials
major basic protein
defensins
Fever
Leukocytosis
C-reactive protein positive
Cloudy swelling of parenchymatous organs