LO: Describe the key features of acute inflammation including the vascular reaction, leukocyte recruitment-activation, actions of the principal mediators of inflammation and outcomes

Acute inflammation

• Inflammation - response of vascularised tissues that delivers leukocytes and molecules of host defence to sites of infection and cell damage
• Without inflammation - infections would go unchecked, wounds never heal and injured tissues remain as permanent open sores
• Neutrophils are main acute inflammatory cell - appearing within hours of trigger
• Heat, Redness, Swelling, Pain, Loss of function
• 5 hard Rs: Recognition, Recruitment, Removal, Regulation, Resolution

Recognition

• Infection (pathogen associated molecular patterns PAMPs/MAMPs, non-self molecules)
• Necrosis (damage associated molecular patterns DAMPs, structures from self following damage)
• PAMPs and DAMPs recognised by sentinel cells (macrophages, mast cells and dendritic cells)
• Sentinel cells activated by DAMPs/PAMPs - release inflammatory mediators

Mast cells

• Widely distributed throughout connective tissue
• Activation by: tissue trauma, complement proteins (C3a and C5a), cross-linking of cell surface IgE by antigen
• Response by release of preformed histamine granules - vasodilation of arterioles and increased vascular permeability
• Delayed response by production of arachidonic acid metabolites - particularly leukotrienes

Complement pathway

• Plasma proteins
• Exist in inactive form
• Activated - act as enzymes to activate the next protein in the chain
• Cascade - one activates the next which activates the next and so on.
  
• Allows process to be activated at the beginning with numerous interactions before reaching end point
• Complement pathway is activate by microbes and in multiple ways
• More than 20 proteins: C1-C9
• Numbered in order of discovery than order they work
• Complement proteins participate in both innate and adaptive immunity
• Cleavage of C3 to C3a to C3b is a key step in all three pathways

Classical pathway

• Relies on antibodies - adaptive immune system
  

Alternate pathway

• C3 binding directly to microbe - no antibodies so innate immune system

Lectin pathway

• Some microbes express carbohydrates on their cells
• Activated - Mannose binding lectin this then activates C3

Effector function

Kinin system

• Component of acute inflammation
• Also a plasma protein cascade
• Endothelial damage exposes collagen to the factorXII (Hageman factor)
• Collagen activates factorXII
• Activates factorXII(a)
  • Initiates clotting cascade - coagulation
  • Initiates kinin system - production of bradykinin

Bradykinin

• Mediator of inflammation
• Bradykinin increases the leakiness of blood vessels - causing swelling
• Endothelial cells contracting increasing the space between cells
• Sensitise nerve endings causing pain

Prostaglandins and leukotrienes

• Lipid mediators
• Produced from arachidonic acid (AA)
• Stimulate vascular and cellular reactions in acute inflammation
• Importance of these AA-derived mediators has lead to development of drugs to inhibit their production

Reaction of blood vessels

• Vasodilation: increased blood flow, brings more inflammatory cells to the site of injury - redness and heat
• Increased permeability of micro-vasculature: allows protein-rich fluid and inflammatory cells to move into the interstitial tissue - swelling/loss of function
• Stasis: reduced fluid within vessels and increased diameter leads to slower blood flow. Neutrophils accumulate along the endothelial lining, adhere and migrate

Neutrophils

1. Margination
2. Rolling
3. Adhesion
4. Transmigration and chemotaxis
5. Phagocytosis
6. Destruction of phagocytosed material
7. Resolution

• Bacterial products, IL-8, C5a and LTB4 are strong chemoattractants
• Half life of 6-8 hours
• Degranulation (pro-killing effectors and pro-inflammatory cytokines)
• Phagocytosis
• NETosis (neutrophil extracellular traps)

Phagocytosis and O₂-dependent killing

• Opsonins - C3b
• Pseudopods extend from the neutrophil to form phagosomes - internalised and merge with lysosomes to produce phagolysosomes
• Destruction of ingested particles within the phagolysosome by lysosymal enzymes, reactive oxygen and nitrogen species
• O₂-dependent killing is the most effective mechanism for killing phagocytes

Degranulation

• Neutrophils release antimicrobial substances stored inside intracellular granules into a phagosome or into the surrounding tissue
• Help fight extracellular pathogen
• Excessive release - cause damage to surrounding host tissues

NETosis

• Trap and kill microbes
• Releasing a web of their own DNA and antimicrobial proteins
  
• Sticky extracellular trap that can capture bacteria, fungi and other pathogens

Resolution

• Neutrophils die by apoptosis
• Disappear within 24 hours after stimulus has been eliminated
• After the neutrophilic phase ends, the era of macrophage begins

Macrophages

• Peak 2-3 days after inflammation begins
• Derived from monocytes in blood
• Ingest via phagocytosis - helped by opsonins
• O₂-independent killing, using lysozyme
• Main controllers of the next steps in the inflammatory process

Outcomes

• Resolution and healing
  • Anti-inflammatory cytokines (IL-10 and TGF-beta) produced by macrophages
• Continued acute inflammation
  • IL-8 produced by macrophages recruits more neutrophils
• Abscess formation
  • Cytokines and fibrogenic growth factors produced by macrophages
• Chronic inflammation
  • Macrophages activate CD4+ helper T cells

Systemic effects

• Fever: cytokines (TNF, IL-1) stimulate production of prostaglandins in the hypothalamus
• Leukocytosis: release of cells from the bone marrow, cytokines stimulate production of leukocytes from precursors in bone marrow
• Production of acute-phase proteins: C-reactive protein
• Septic shock: fall in blood pressure, disseminated intravascular coagulation, metabolic abnormalities - induced by high levels of TNF and other cytokines