85. Tissue injury, inflammation, lymphatic circulation

Inflammation is the major sign of infection. It’s the non-specific defence reaction against damaging effects, so-called noxious stimuli. A noxious stimulus is any damage-inducing effect.

The classical basic signs of inflammation are:

• Calor – warmness
• Rubor – redness
• Tumor – swelling
• Dolor – pain
• Functio laesa – loss of function

Nowadays we consider inflammation as a pathological process and not by the morphological signs.

Etiology

Exogenous noxious stimuli

• Mechanical
  • Physical trauma
  • Foreign body
  • Surgery
• Physical
  • Heat
  • Cold
  • UV
  • Electromagnetic radiation
  • Ionizing radiation
• Chemical
  • Acids, bases
  • Organic solvents
  • Pollution
  • Plant poisons
• Biological
  • Bacteria
  • Virus
  • Fungi
  • Protozoa
  • Parasites

Endogenous noxious stimuli

• Perfusion anomalies
  • Ischaemia
  • Reperfusion injury
• Autoimmunity
• Endogenous toxins
  • Ammonia
  • Uraemic toxins
• Prematurely activated proteases
  • DIC
  • Acute pancreatitis
  • ARDS

Mechanism

• Vascular changes
  • Arterial dilation + venous constriction -> hyperaemia -> rubor, calor
  • Histamine release from mast cells -> Increased capillary permeability
    • Local oedema formation -> tumor (swelling)
  • Leukocytes
    • Rolling on the endothelium
    • Adhesion on the endothelium
    • Diapedesis – leukocytes cross the endothelial wall
• Cell infiltration – leukocytes extravasate into tissue
  • First neutrophils, then monocytes (which differentiate into macrophages), lastly lymphocytes)
  • Leukocytes produce pro-inflammatory cytokines -> dolor
  • Leukocytes phagocytose and kill by other mechanisms
• Tissue death and later reparation

An inflammation should normally involve a balance of pro-inflammation and anti-inflammation. If there is excessive pro-inflammation a condition called systemic inflammatory response syndrome (SIRS) occurs. If there is excessive anti-inflammation a condition called compensatory anti-inflammatory response syndrome (CARS) occurs.

Molecular mediators of inflammation

The monoamines include serotonin and histamine, where histamine is more important. It’s released from basophils and mast cells, and increases vascular permeability, induces pain, causes itching, attracts mast cells and stimulates cytokine production.

The most important peptides and proteins are:

• Coagulation inhibitors
• Chemokines
• Cytokines
  • IL-1
  • IL-6
  • TNF-α
• Complement system
• Fibrinolytic system

The arachidonic acid derivates are the prostaglandins, leukotrienes and thromboxanes. They’re produced by from arachidonic acid by the enzymes cyclooxygenase and lipoxygenase. They mediate many effects like chemotaxis, increased capillary permeability, fever, and vasodilation.

Other important pro-inflammatory molecules are:

• NO – causes vasodilation
• Reactive oxygen species – produced by leukocytes to damage target cells or pathogens
• Angiotensin
• Adhesion molecules

NF-κB is the most important transcription factor in inflammation. It is found in virtually all cell types. It can be activated by:

• Pro-inflammatory cytokines – like IL-1 and TNF-α
• Pathogens – like viruses, bacteria
• Physical noxious stimuli
• Oxidized LDL
• Advanced glycation end-products – which is present in diabetes mellitus
• Hypoxia
• Reperfusion

This transcription factor controls and activates the genes for basically every protein you can imagine being important in inflammation, like:

• Pro-inflammatory cytokines – like IL-1, IL-6, TNF-α
• Cell adhesion molecules – like selectins and integrins
• Immune-related receptors – like MHC I, MHC II
• iNOS – produces NO
• Cyclooxygenase
• Matrix metalloproteinases (MMPs)

Anti-inflammatory mediators

The body produces many anti-inflammatory molecules, like:

• Anti-inflammatory cytokines – like IL-4, IL-10
• Testosterone
• Soluble cytokine receptors – these receptors bind to and inactivate pro-inflammatory cytokines

Many pharmacological agents exert anti-inflammatory effects:

• NSAIDs – inhibit cyclooxygenase
• Antibodies against cytokines – they bind to and inactivate pro-inflammatory cytokines
• Soluble cytokine receptors
• Glucocorticoids – inhibits NF-κB
• ACE inhibitors – decreases the level of angiotensin

Sickness behaviour

When we are sick we act differently than when we’re not. We’re weak, tired, depressed and hurting. It involves:

• Fever
• Anorexia (lack of appetite)
• Tiredness
• Social withdrawal
• Avoidance of interaction
• Somnolence
• Depression

These reactions are deliberate by the CNS. The goal is to spare energy to fight infection, not waste energy on unnecessary moving and limit excessive inflammation. Sickness behaviour is mediated mostly by IL-1 and IL-6.

Chronic inflammation

Chronic inflammation occurs if the immune system cannot get rid of the noxious stimulus (often a pathogen), or in case of autoimmune reactions. Monocytes, macrophages, lymphocytes and plasma cells are especially involved. The distinctive pattern of chronic inflammatory reaction is granulomatous inflammation, which involves a form of activated macrophages called epithelioid cells.

The following conditions are associated with chronic inflammation:

• Obesity
• Diabetes
• Metabolic syndrome
• Atherosclerosis
• Heart failure
• Dementia