- What 3 essential roles does inflammation play in combating infection
- Delivers additional effector molecules and cells to the site of infection
- Provides a physical barrier (microvascular coagulation) preventing the upstream spread of infection
- Promotes repair of injured tissue
- Give a brief description of the mediators of inflammation
- Exogenous mediators
- Bacterial toxins and products (LPS): complement activation, hageman factor, T-cell proliferation
- Peptide fragments present plasma in inactive form: complement, kinin, fibrinolytic, clotting system
- Endogenous mediators
- Preformed mediators: Histamine, Serotonin
- Products produced by cells at the site of injury: PGE2, LTE4
- Functions
- Increased vascular permeability: Histamine, Serotonin, Bradykinin, C3a, C5a, Prostacycline
- Smooth muscle contraction: Histamine, Serotonin, Bradykinin, C3a, C5a
- Pain: Bradykinin, PGE2
- Vasoconstriction: TXA2, LTB4
- Increased endothelial adhesiveness: IL-1, TNF-a, Endotoxin
- Mast cell degranulation: C3a, C5a
- Pyrogens: IL-1, TNF-a, PGE2, IL-6
- Production of ROS: C5a, TNF-a
- Exogenous mediators
- Describe phagocytosis and the respiratory burst
- Phagocytosis is an active process done by macrophages and neutrophils.
- The bound pathogen is surrounded by the phagocyte membrane and then internalized in a membrane bound vesicle termed the phagososme.
- The phagosome becomes acidified killing the pathogens or it can fuse with lysosomes to form the phagolysosome
- Nitric oxide, superoxide anion and hydrogen peroxide are used to kill the engulfed microbes.
- Superoxide is generated by NADPH via the respiratory burst → NADPH oxidase converts O2 to superoxide ions → SOD converts superoxide to hydrogen peroxide → Myeloperoxidase and iron convert the hydrogen peroxide and chloride ions to hypochlorite ions and hydroxyl radicals.
- What roles do Pattern recognition receptors play in the immune system
- Phagocytic transmembrane receptors: Mannose receptor
- Opsonisation and complement activation: Mannose binding lectin
- Link microbial recognition to proinflammatory signals: TLRs, NLRs, RIG-1-like receptors
- TLRs contain and extracellular domain with a series of leucine rich repeats and an intracellular domain with a conserved signalling module called Toll/IL-1 receptor domain. It is expressed by macrophages, neutrophils and DCs. They link recognition of conserved components of bacteria, viruses, fungi and protozoa to activation of these cells.
- Cytosolic PRRs detect pathogens that enter host ells. They are more varied in structure and function that TLRs and are collectively referred to as nucleotide-binding oligomerization domain-like receptors (NOD-like receptors). Cytosolic PRRs can also sense nucleic acids i.e. Retinoic acid inducible gene (RIG-1) and their receptors referred to as RIG-1-like receptors.
- Describe the phases of inflammation
- Recognition of infection: Resident cells (Macrophages, DCs) engulf and detect microbial organisms via PRRs. Mast cells are impicated in the early phase of inflammation through their release of cytokines and preformed mediators. Net result of pathogen recognition is activation of resident phagocytes, mast cells and the release of pro-inflammatory cytokines and preformed mediators
- Recruitment of inflammatory cells**:** Cytokines and other pro-inflammatory mediators induced changes in local blood vessels and endothelial cells that promote conversion of the infected tissue to an inflammed state. TNF-a, IL-1 and Lipid mediators collectivly lead to increased leukocyte transmigration and blood flow to the infected sites. Neutrophils arrive within hours followed by an influx of monocytes.
- Elimination of the microbe: TNF-a causes degranulation of neutrophils into the ECM. These granules can cause significant damage to host tissues and cells (elastase, Cathepsin G, Proteinase 3) Macrophages engulf the neutrophils and microbial organism, degrading them using proteases and antimicrobial peptides
- Resolution of inflammation: Lipoxins, protectins and resolvings send anti-inflammatory signals that promote resolution and repair. Lipoins stop neutrophil influx, promote uptake of apoptotic neutrophils and recruit additional monocytes. Macrophages, neutrophils and epithelial cells produce secretory leukocyte protease inhibitor SLPI that inactivates the proteases released from neutrophil granules and this pushes the inflammatory response towards resolution.
- Briefly describe sterile inflammation
- Sterile inflammation results from cells that die from tissue damage, triggering and inflammatory response that shares many features with inflammation induced by infection.
- Etiology of sterile inflammation
- Trauma
- Ischemia
- Ischemia reperfusion
- Complications
- Circulatory shock
- Multiple organ failure
- Endogenous molecules released when cells die by necrosis (indicative of sterile cell injury)
- Heat shock proteins
- Hyaluronan
- B-defensin
- Uric acid crystals
- What is the clinical relevance of inflammation
- Chronic granulomatous disease: Failure to produce ROS (NADPH oxidase deficiency)
- Increased risk of infection with encapsulated organisms (SHiNE): Inherited defects in the ability to produce terminal complement components C5-C9
- Allergies: Type I hypersensitivity reactions
- Autoimmune disease: Failed tolerance
- Transplantation and tissue rejection: Histocompatibility
- Chronic inflammation as a cause of cancer:
- ROS released during inflammation is a powerful DNA damaging agent.
- Increased mitosis in response to inflammation puts more cells at risk of mutations during S phase replication
- Suppression of apoptosis in inflammed tissues allows cells with precancerous mutations to live or grow into full blown cancer
