vascular and cellular events of inflammation

first cell responders during inflammation

macrophages

dendritic cells

mast cells

macrophages, dendritic cells, mast cells release what mediators

amines and cytokines

amines and cytokines will recruit

leukocytes: monocytes and granulocytes and plasma proteins (complement, kinins and others)

leukocytes: monocytes anad granulocytes will

phagocytose and eliminate microbes and dead tissue

edema will also occur

once elimated the microbes

cytokines will still be released and fibroblasts for tissue repair

acute inflammation: vascuar fluidic phase is divided in 4 stages

transient vasoconstriction

vasodilation

increased vascular permeability

slowing and stasis of blood flow

transient vasoconstriction

not always seen, immediate and lasting a few seconds

primarily a neurogenic/direct endothelin response

transient vasoconstriction occurs in

precapillary sphincters

vasodilation and increased blood flow

consistently observed with inflammation

responsible for rubor and calor

opens capillary beds

blood vessels get distended by blood

ACTIVE HYPEREMIA

vasodilation will cause the opening of

pre-capillary sphincters

there are 2 types of mediators in vasodilation

early

late

early mediators for vasodilation

vasoactive amines: hitsamine and serotonin

late mediators for vasodilation

prostaglandins: PgD, PgE,prostacyclin

nitric oxide

increased vascular permeability:vascular leak

progresses from transudate-exudate

dilutes,confines, isolate stimulus

causes swollen lymph nodes

increased vascular permembility occurs in 2 stages

early

late

acute inflammation: vascular fluidic phase is divided in

transient vasoconstriction

vasodilation

increased vascular permeability

slowing and stasis of blood flow

transient vasoconstriction

not always seen, immediate and lasting only a few seconds

caused by constriction of the precapillary sphincters

primarily a neurogenic/direct enothelin response

example of transient vasoconstriction

delay of bleeding from a sharp cut

vasodilation and increased blood flow = active hyperemia

consistently observed with inflammation

responsible for rubor/redness and calor/ heat

relaxation of the precapillary sphincters

opens capillary beds

blood vessels will get distended by blood

2 stages of vasodilation mediators

early

later

later vasodilation mediators

prostaglandins = PgD, PgF, prostacyclin

nitric oxide

in increased vascular permeability it will progress from

transudate - exudate - inflammatory edema

serves to dilute, isolate, confine stimulus

causes swollen lymph nodes

early vascular permeability

protein-poor fluid transudate

INCREASED hydrostatic pressure

slower blood flow

congestion

later vascular permeability

chemical mediators affect the endothelial cells causing contraction and increased gaps between cells

primary site of action of the later vascular permeability

post-capillary venules

mechanisms of vascular leak

retraction of endothelial cells

endothelial injury

leukocyte-mediated vascular injury

increased transcytosis

vascular leak: retraction of endothelial cells

occurs mainly in venules

induced by HISTAMINE

rapid and short lived

vascular leak: endothelial injury

in arterioles, capillaries, venules

caused by burns, microbial toxins

rapid: hours to days

vascular leak: leukocyte mediated vascular injury

occurs in venules, pulmonary capillaries

assoc. with late stage of inflammation

long lived hours

vascular leak: increased transcytosis

occurs in venules

mediated by VEGF

edema: transudate

low protein levels

fluid accucmulation due to hydrostatic imbalances between intravascular and extravascular compartments depsite normal vascular permeability

clear,colorless, slightly yellow

edema: exudate

high protein levels

related to increased vascular/endothelial permeability

caused by leakage of plasma proteins = albumin and leukocytes

cloudy to opaque

permeability mediators

vasoactive amines

complement fragments = C3a C5a

bradykinin = pain inducer

leukotrienes = LTC 4, LTD 4, LTE 4

platelet activating factor

cytokines

substance P

blood flow slowing/stasis

secondary effect of the combination of vasodilation and increased permeability, decreasing fluid content

causes loss of laminar flow in the capillaries and allowa the margination of leukocytes

slowing of blood flow breaks leukocyte arrangement and allows leukocyte sto go toward periphery of blood vessels

macrophages with microbes induce the activation of

cytokines and chemokynes

cytokines and chemokynes will induce the activation of

integrins= protein cell receptors allowing the adherence of leukocytes

acute inflammation: cellular phase

delivers phagocytic cells to engulf, neutralize and remove stimulus

cellular phase can be divide in

margination

rolling

adhesion

chemotaxis

rollling of polymorphonuclear cells is

loose transient adehsion between leukocytes and endothelium, mediated by surface expression of pre-formed selectins

rolls along endothelial lining

firm adhesion of leukocytes

induced de-novo production of adhesion molecules on EC of immunoglobulin superfamily: VCAM-1, ICAM-1-2-3

MEDIATORS OF firm adhesion of leukocytes

IL-1

TNF

IL-6

bacterial LPS

integrins are where?

on leukocyte surface

in form adhesion, integrins will adhere to

immunoglobulins on EC

mediators for the expression of integrins on leukocytes

PAF

chemokines = IL8

chemotaxins

cause cytoskeletal reorganization and extension of pseudopodia in direction of concetration gradient = ameboid crawl

during emigration and chemotaxis

adhesion molecules along EC intracellular gaps adhere to extracellular matrix proteins in tissues

chemotaxins can be

endogenous

exogenous

endogenous chemotaxins

chemokines

• CX-C ALPHA: IL-8/CXCL8 = attract neutrophils

• C-C chemokynes beta = attract WBC

• LTB 4, HETE, PAF

• NECROTIC CELL DAMP’s

• plasma: C5a, fibrin degeneration products

exogenous chemotaxins

bacterial peptides with terminal N-formylmethionine

basically, the cellular phase is the triggering of

leukocytes adhesion cascade

leukocytes adhesion deficiency affects

Holstein cows

irish setters

humans

LAD is caused by

point mutations on B-integrins on leukocytes

neutrophilia occurs without transmiggration

LAD will cause

recurrent mucosal infections such as

• gingivitis

• gastrointestinbal ulcers

• pneumonia

• cutaneous ulcers

phagocytosis

engulf, kill, remove offender

main phagocytes

macrophages

neutrophils

stages of phagocytosis

recognition and attack

engulfing = phagosome

phagolysosome

respiratory burst

extrusion of debris

in the first stage of phagocytosis, recognition and attack is aided by

OPSONIZATION via:

• Ab

• C3b

• fibronectin

in the second satge of phagocytosis, engulfing is done by

extension of pseudopodia around object

fusion of cellular membrane which creates a phagosome

in the third stage of phagocytosis what occurs?

phagosome + lysosome fusion = phagolysosome

expulsion of lysosome contents into phagolysosome

in the 4th stage of phagocytosis what occurs?

respiratory burst = production of reactive oxygen species and activation of enzymes

BACTERICIDAL

t/f neutrophils are sloppy eaters and short lived in tissue

ture

systemic effects of acute inflammation

fever

decreased apetite

increased slow wave sleep

accelerated release of WBC from marrow

stimulation of colony stimulator factors

protein catabolism

release of acute phase proteins from liver

IL-6 AND 1 + TNF will cause

fever

decreased apetite

increased slow wave sleep

accelerated release of WBC from marrow

stimulation of colony stimulator factors

protein catabolism

release of acute phase proteins from liver

are caused by:

IL-1 + TNF