OIA1010 INFLAMMATION

Type of Inflammation

Chronic: slow (days, months or years), monocytes/macrophages & lymphocytes, often severe tissue injury & progressive fibrosis, less prominent local & systemic signs

Acute: fast (minutes or hours), mainly neutrophils, mild tissue injury & self limited fibrosis, prominent local & systemic signs

Common Inflammatory Condition: Skin Furuncle (boil) - caused by Staphylococcus sp.

Cardinal Signs of Inflammation

Rubor (redness): increased blood flow

Calor (heat): increased blood flow

Tumor (Swelling): leakage of cells & fluid into tissues

Dolor (Pain): increased nerve sensitivity due to chemical mediators

Function laesa (loss of function)

Causes of Inflammation

Infective magnets (bacteria, viruses, parasites)

Foreign bodies (dirt, splinters, suture material, implants)

Immune reactions (allergic, hypersensitivity, autoimmune reaction)

Tissue necrosis (tissue death)

Physical agents (trauma, heat, cold, irradiation)

Chemical agents (drugs, toxins)

Inflammatory Response

(1) Offending agent recognised by host cells & produce chemical mediators

(2) Leukocytes & plasma proteins are recruited from circulation to the site

(3) Activate leukocytes & proteins to destroy & eliminate offending substance

(4) Reaction controlled & terminated and damage tissue is repaired

Vascular Changes

Maximise movement of proteins & leukocytes from circulation to site of infection

Blood Vessel Diameter (Vasodilation)

Action of mediators (histamine) on vascular muscle

Initial constriction (transient)

Arterioles dilate followed by capillary bed expansion

*increased blood flow -> redness & heat

Vascular Permeability

Protein-rich fluid flow out into extravascular tissue (exudate): small molecules first, then fibrinogens and cells

*Increase osmotic pressure in tissue -> swelling (edema)

Retraction of endothelial cells (mediators cause contraction -> gaps appear)

Endothelial injury (direct damage caused by burns & microbial toxins)

Chemical Mediators

Cellular Events

(1) Leukocytes recruited -> activate to eliminate offending agent (phagocytosis)

(2) Neutrophils rapidly recruited -> cytoskeletal rearrangement & enzyme assembly to mount rapid, transient response

(3) Macrophage (slow responders) -> ingest & destroy microbes, necrotic tissue & foreign substances -> produce growth factor (aid recovery)

Leukocyte Emigration

Infectious microbes recognised by macrophages & sub-epithelial dendritic cells -> produce cytokines & chemokines

Cytokines (TNF 7& IL-1): act on endothelium of venues near site of infection -> initiate Leukocyte emigration

Chemokines: provide signals & facilitate movement once they migrate into tissue (chemotaxis)

(1) Loose attachment & rolling of leukocytes

Endothelial cells upregulate expression of adhesion molecules (selectins)

Selectins bind to surface carbohydrates on leukocytes

Repetitive process: tethered to endothelium, flowing blood disrupt binding & bonds reforming downstream

(2) Leukocyte migration

Chemokines stimulate motility of leukocytes -> migrate between endothelial cells along concentration gradient of chemoattractant (ref. below)

(3) Firm adhesion

Integrins express on leukocytes assume high affinity state

Endothelial cells upregulate expression of adhesion molecules ICAM-1 & VCAM-1 that binds to integrins expressed

Firm binding of integrins to ligands arrest rolling, cytoskeleton recognised & spread out on endothelial surface

Chemotaxis

Movement of leukocytes after Emigration towards increasing concentration of chemotactic agent

Chemoattractant: exogenous (bacterial products) or endogenous (chemokines & complement components -C5a)

Leukocyte Activation

Leukocytes (neutrophils & macrophages) require activation to perform function -> able to phagocytosis, lyse injurious particles & release chemical mediators

Phaogcytosis

(1) Recognition & attachment by receptors on macrophage surface

Mannose receptor binds to mannose, fructose on bacteria

Scavenger receptors

Opsonins (IgG, C3 or some lectins)

(2) Engulfment

Pseudopods form -> foreign material incorporate within cell vacuole (phagosome) -> Fusion with lysosome

(3) Killing & Degradation

Done by reactive oxygen species (ROS), nitric oxide, lysosomal enzymes

Sequelae of Phagocytosis

Neutrophils (1-2 days)

Lysosomal enzymes discharge into vacuole

Oxidising agents kill or digest bacteria

Neutrophil degranulate released enzymes may cause injury

Virulent bacteria may resist killing

Bacteria free as cell death -> can further damage

Macrophages (months - years)

Mostly success eliminate

Bacteria persist: remain or move via lymphatics to other areas

ALL debris gradually removed

Antigenic material presented in immune system

Release enzyme, oxidising agents into tissues -> ongoing damage (rheumatoid disease)

Chemical Mediators

Outcome of Acute Inflammation

Ideal outcome: harmful agent eliminated, damage tissue return to normal -> resolution

Complete restoration of tissue after acute inflammation:

Minimal tissue damage and cell death

Damaged cells able to regenerate

Causative agents rapidly eliminated

Local conditions favor removal of exudate

Process of Resolution

Fibrin & other proteins dissolve by fibrinolysin and enzymes produced by neutrophils & macrophages

Fluid removed in blood & lymphatic vessels

Removal of all debris by phagocytes to lymph nodes

Blood flow returns to normal