Inflammation

living organisms

• Initial rapid response

• Develops within minutes or hours

• Lasts for short period of time

• Inflammatory cells: neutrophils

• Usually follows unhealed or untreated acute inflammation or rise de novo

• It takes days or weeks to develop

• Lasts for long period of time

• Inflammatory cells: lymphocytes, macrophages

produced by hsot cells & plasma proteins

induce & regulate inflammation

heat

redness

swelling

pain

loss of function

infection and microbial toxins

epithelial cells

macrophages

dendritic cells

leukocytes

-> express TLRs

(1) dilation of small vessels, leading to an increase in

blood flow

(2) increased permeability of the microvasculature, enabling plasma proteins and leukocytes to leave the circulation

(3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent

exudation

• Extravascular fluid

• High protein concentration

• Cellular debris

->Increase in permeability of blood vessels during inflammation

=> EDEMA

rich in proteins and acute inflammatory cells

• Extravascular fluid

• Low protein concentration

• Little or no cells , low specific gravity

-> Osmotic or hydrostatic imbalance BUT the vascular permeability is normal

=> EDEMA

clear sterile filrate of blood

neutrophil and macrophages

1. margination

2. rolling

3. adhesion

4. transmigration

WEAK ADHESION

• Mediate the initial weak interactiones between leukocytes and endotheium (E, P, L), expression of selectin depends on the state of endothelial cells and inflammatory mediators

• Express on the surface of cells only when activated by endothelial injury, cytokines,...

• Important for the process of rolling and slowing down the leukocytes

FIRM ADHESION

• Mediate firm adhesion of leukocytes to blood vessel wall

• Adhesion of leukocytes to endothelial cells

• Adhesions of various cells to extracellular matrix

• Integrins on the surface of leukocytes have low-afinity for ligands, they have to be activated by chemokines

postcapillary venules

important step in binding leukocytes to endothelium and transmigration process

enzymes secreted by leukocytes in extravascular space

locomotion along a chenical gradient

• Bacterial products

• Cytokines

• Component of complement (C5a)

• Leukotrien B4

1. Recognition and attachment of the particle to be ingested; manose receptors (sugars

   in the bacterial wall), scavanger receptors (LDL microbe particles) and opsonins receptors (IgG and C3b)

2. Engulfment; formation of phagosome and phagolysosomes

3. Intracellular destruction of microbes nad debris; ROS, NO, lysosomal enzymes, granular enzymes

actively secreted

• Specific (secondary) granules packed with lysozme, collagenase, gelatinase,...

• Azurophil (primary) granules packed with MPO, bactericidila factors,..

anti-protease in the serum and tissue fluids like α1-anti-trypsin

extracellular fibrillar networks that concentrate anti-microbial substances at sites of infection and prevent the spread of the microbes by trapping them in the fibrils

Histamine

Prostaglandins

Cytokines

Chemokines

Platelet-activating factor

Complement

Kinins

• Histamine and Serotonin

• Stored in cells as preformed molecules in an active form

• Produced by mast cells in the tissue, but also basophils and platelets in the blood

• Released after degranulation of cells

  -> physical injury

  -> binding of antibodies to mast cells

  -> complement products called anaphylatoxins

stimulation of endothelial retraction -> higher permeability

dilation of arteriloles

short action

binds to H1 receptor on endo cells

H1 receptors

vesoactive mediator in paltelets and neuroendocrine cells, GI tract

neurotrasmitter in GI

VASOCONSTRICOR

• Arachidonic acid is derived from phospholipids through the action of phospholipases.

• Arachidonic acid is further metabolized through two pathways:

  •Lipoxygenase pathway -> leukotriens and lipoxins •Cyclooxygenase pathway -> prostaglandins

=> bind to G protein-coupled receptors on many cell types and can mediate virtually every step of inflammation

• Mainly produced in mast cells, macrophages and endothelial cells

• COX-1, COX-2 ØPGE2, PGD2, PGF2a, PGI2 (prostacyclin), and TXA2 (thromboxane A2)

• Pain, fever

• Note the opposite effects of prostacyclin and thromboxane A2!!!

• produced in leukocytes and mast cells by the action of lipoxygenase and are involved in vascular and smooth muscle reactions and leukocyte recruitment.

• Multiple steps in leukotrien production

• LTB4 important for chemotaxis,activation of neutrophils and stimulation of ROS production

• LTC4 , LTD4 and LTE4 are important for vasoconstriction and bronchospasm

• Duration -> acute or chronic

• Etiology -> infectious, chemical, physical or immune causes

• Location -> localized or widespred

• Pathologic features

vasodilation, accumulation of leukocytes, Oedema

• Serous inflammation

• Fibrinous inflammation

• Purulent inflammation

• Ulcerative inflammation

• Pseudomembranous inflammation

• Chronic inflammation

• Granulomatous inflammation

• Early stage of most inflammation (e.g., pneumonia,...)

• Viral infection of skin vesicles in herpesvirus infection

• Joint swelling in rheumatoid arthritis

Marked by exudation of EC serous fluid -> effusion

• Increased↑vascular leaks

• Localprocoagulant stimulus

High molecular proteins such as fibrinogen pass out of the blood

• Fibrinous exudate is characteristis of inflammation in the lining of body cvities such as pericaridium or pleura

• Eosinophilicmeshworkor amorphous coagulum

• Dissolvedbyfibrinolysisand cleared by macrophages

• Ingrowth of granulation tissue – leads to scarring

• Obliterationofpericardialsac

pus

neutrophils

debris of necrotic cells

Oedema fluid

diffuse purulent inflammation

localized purulent inflammation

localized collection of pus

local defect of the surface of an organ or tissue (hole)

• acute: -> intense polymorphonuclear infiltration and vascular dilatation in the margins and base

• chronic: -> mononuclear infiltration and fibrosis

• Mononuclear cells infiltration

• Tissue injury – destruction

• Attempts of healing - repair by fibrosis and angiogenesis

• persistent infection

• hypersenitivity disease (autoimmune)

• prolonged exposure to toxins

The granuloma consists of:

• Epithelioid cells (activated macrophages)

• Lymphocytes

• Multinucleated giant cells

• Sacroidosis

• Chrons disease

• Foreign body geanuloma

langhans giant cells

can readily regenerate after

injury as long as stem cells are preserved.

cells are normally in the G0 stage, but they can divide in response to injury

terminally differentiated nonproliferative cells

regenerates from progenitor cells

very fast

replacement of injured tissue by ct if its not capeble of regeneration

• Polymorphonuclear leukocytes

• Macrophages (central cellular players in the repair process)

• Myofibroblasts

• Fibroblasts

• Angioblasts

• Epithelial cells

formation of new blood vessels

critical in healing

newly formed vessels are leaky (incomlete interendothelial junctions) -> edema

1. Inflammatory cells

2. Proliferation of fibroblasts

3. New thin-walled capillaries

4. Loose extracellular matrix

• Defects in healing:

-> Chronic wounds (venous leg ulcers, diabetic ulcers, pressure sores, arterial ulcers)

• Deficient scar formation -> Dehiscence

• Excess scar formation -> Keloid /hypertrophic scar –> Contractures –> Exuberant granulation

• Induced by microbial products

• TLRs and IFN-y play important role

• M 1 macrophages produce NO and ROS

• Important role in host defense against microbial pathogens

• Tlymphocytes, IL-4, IL-13

• M 2macrophages stimulate tissue repair

• secrete growth factors that promote angiogenesis, activate fibroblasts, and stimulate collagen synthesis

TBC

• Persistent Tcell mediated response to an antigen thant can't be easily removed (microbe or self-antigen)

• Tlymphocytes, IL-2, IFN-y

• Inflammatory response to inert foreign body

• ABSENT Tcell-mediated immune responses

• Talc, surgical material,...