inflammation (L16)

define acute inflammation

the process of inflammation through which our bodies tissues initially respond to infection or injury

local clinical features of acute inflammation

redness - caused by vasodilation - histamine and prostaglandin

swelling - caused by inflammatory exudate from increased vascular permeability - histamine and leukotrienes

heat - caused by vasodilation - histamine and prostaglandin

pain - caused by tissue damage - prostaglandin and bradykinin

loss of function - caused by tissue damage - ROS, NO, lysosomal enzymes

what are three patterns of acute inflammation

purulent (supparutive) inflammation

serous inflammation

fibronous inflammation

purulent inflammation

characterised by the production of pus (an inflammatory exudate rich in neutrophils and fluid and liquified debris of necrotic cells)

caused by pyogenic organisms that cause tissue necrosis and liquefaction

abscess is a localised collection of pus

serous inflammation

characterised by a fluid-rich, cell poor exudate

occurs in peritoneum, pleura, pericardium

other examples: skin blister or a runny nose

fibrinous inflammation

characterised by a fibrinogen-rich exudate and fibrin deposition

seen in pericardium, peritoneum

usually a part of coagulation cascade (fibrin to fibrinogen)

steps in acute inflammatory response

1. recognition - pattern recognition receptors and vascular changes

2. recruitment - of leukocytes

3. removal of the agent - killing and degradation - ROS/NO and phagocytosis

4. resolution

two types of sentinel cells important in acute inflammation (recognition)

macrophages and mast cells

macrophages

monocytes which differentiate in the tissue

long lived in tissue

phagocytic

produce pro-inflammatory cytokines in response to damage or pathogens

mast cells

tissue resident cells that can be long lived

contain numerous granules

release chemical mediators such as histamine, leukotrienes and prostaglandin

released chemicals mediate vaascular changes, pain

mast cells can survive degranulation

pattern recognition receptors - what

on macrophages and mast cells (sentinel cells in the tissues)

detect DAMPs (damage associated molecular patterns) and PAMPs (pathogen associated molecular patterns) 

what does detection of DAMPs cause release of

proinflammatory cytokines including

• TNF alpha

• IL-1beta 

• IL-6

what does detection of PAMPs cause release of

chemical mediators including:

• histamine

• prostaglandin

• leukotrienes 

acute inflammation can be measured by

increased temperature

increased acute phase proteins in serum (e.g. C-reactive protein, fibrinogen - measured by erythrocyte sedimentation rate)

increased neutrophils in blood 

macrophages and mast cells in tissues produce

prostaglandin - vasodilation

leukotrienes - vascular permeability 

histamine - vasodilation and vascular permeability

vascular changes - WBCs

normally occassional resident lymphocytes or macrophage

inflamed = increased blood flow → leakage of plasma proteins = odema → neutrophil emigration 

increased vascular permeability

inflammation causes dilation (so more blood) and retraction of endothelial cells

so fluids and proteins can pass 

neutrophils

large granular cells with a multi-lobed nucleus

recruited into tissues in response to inflammatory cytokines (e.g. IL-1beta and TNF alpha) 

phagocytic 

make up 40-70% of white blood cells in peripheral blood 

short-lived half-life 4-10 hours in circulation, 1-2 days in tissue 

monocytes

large cells with kidney shaped nucleus

phagocytic 

produce pro-inflammatory cytokines (IL-1beta, TNF alpha)

make up 2-10% of peripheral blood mononuclear cells 

circulation time 20-40 hours in blood 

diapedesis 

the process of the cells in the blood moving through the endothelial wall of the vessel to the tissues 

movement of leukocytes from the blood into the affected tissue

1 cytokines produced by macrophages in tissues

2 vessels become leaky and sticky 

3 margination - slower blood flow and increased viscocity (congestion) throws leukocytes at the vessel wall 

4 rolling - leukocytes attracted by chemokines/cytokines 

5 adhesion - leukocytes tick to vessels 

6 diapedesis - leukocytes migrate through vessels 

7 chemotaxis - leukocytes attracted by chemokines esp IL-8

kinetics of acute inflammation

first is edema, then neutrophils, and then monocytes/macrophages

removal - what

destruction of microbes and other offenders through phagocytosis or intracellular killing 

macrophages and neutrophils - how removal

ROS, NO, lysosomal enzymes → microbial actions, phagocytosis and killing of bacterial and fungi

the complement system - what

soluble proteins and their membrane receptors

host defense against microbes, removal of particulate substances (damages cells, microbes, immune complexes), modulation of immune response 

leads to inflammation, lysis, and opsonisation 

the complement system - types

opsonisation

complement components bind to microbes

agglutination 

microbes are stuck together using complement

phagocytic cells have complement receptors; opsonisation and agglutination enhance phagocytosis, increasing clearance of pathogens

lysis

formation of membrane attack complex, perforating the cell wall and release of contents

kills the target organism

inflammation

binding of complement to leukocytes increases adhesion to endothelium

increased chemotaxis (cell migration); macrophages and neutrophils are recruited

osteomyelitis

inflammation of the bone

neutrophils to the site

spread to the periosteum 

subperiosteal abcess may form and impair blood supply causing necrosis 

dead bone can be released into the sinus tract 

resolution 

inflammation decline when offending agents removed 

• chemical mediators have a short half lide and are destroyed by degradative enzymes 

• neutrophils have a short lifespan in the blood, die and are themselves phagocytosed

• activated macrophages secrete IL-10 which downregulates macrophage responses

acute inflammation outcomes

acute inflammation → healing process → resolution or scarring or unhealed wound (ulcer) 

OR 

acute inflammation → chronic inflammation → unhealed wound (ulcer) 

what cause chronic inflammation

prolonged response to persistent stimuli

persistent infections, e.g. mycobacteria, fungi, parasites

immune mediated diseases - asthma, IBD, RA, MS

prolonged exposure to toxic agents (e.g. asbestos, silica)

features of chronic inflammation

inflammatory cell infiltrate

tissue disruption

connective tissue deposition

chronic inflammation mainly mediated by what cells

macrophages and lymphocytes

cellular infiltrate consists of:

macrophages, lymphocytes, plasma cells, other leukocytes

both cell types produce cytokines that drive inflamation and activate each other

macrophage/T cell bidirectional activation

other WBC involvement in chronic inflammation

B cell activation results in plasma cells that secrete antibody into the blood/tissue 

antibody can bind to cells/cell receptors and trigger inflammation 

mast clls accumulate in chronically inflamed tissue and secrete vasoactive an dpro-inflammatory mediators 

eosinophils contribute to initiation and modulation of inflammation 

granulomatous inflammation

distinct pattern of chronic inflammation

granuloma attempt to contain infecting agent

if caused by pathogen usually see a necrotic centre

centre surrounded by macrophages and epitheloid cells which are surrounded by lymphocytes

epitheloid cells can fuse to form large giant cells

epitheloid and giant cells are types of macrophages

conditions associated with granulomas

infectious disease: tuberculosis, leprosy, brucellosis, syphilis, mycotic infections

autoimmunity/autoinflammation: sarcoidosis, chrons disease