Red - Immune Cells Flashcards
What is an endotoxin?
- Cell wall component of gram-neg bacteria
- Potent mediator of septic shock
What region of endotoxins is most responsible for their toxicity?
- Lipipolysaccharide consisting of:
1) O-Antigen/Side Chain
2) Core
3) Lipid-A
*Lipid-A = region most responsible
What is the host response to endotoxins?
- Activation of macrophages
- Activation of complement cascade
- Activation of coagulation cascade
- Release of TNF-alpha, IL-1, IL-6, PAF, NO, various oxidants
- Renal failure (nephrotoxin)
What activates the complement cascade?
- Classical pathway: Fe regions IgG/IgM
- Alternative pathway: directly by sp. pathogens
- Infection
- Shock
- Tissue Injury
What are the most potent components of the complement cascade?
- C3a
- C5a
What are the effects of C3a and C5a?
- C3a, C4a, C5a = anaphylatoxins, proteins bind surface mast cells/basophils–>cell degranulation
- release of histamine from basophils and mast cells: vasodilation, increased permeability (allows IgG/complement to leave blood–>tissues), bronchoconstriction
- C5a = chemoattractant for neutrophils and mononuclear phagocytes
- Stimulate IL-1 release
What are eicosanoids?
Inflammatory mediators primarily generated by hydrolysis of membrane phospholipids by phospholipase A2 + converted to: leukotrienes, PG, prostacyclin, thromboxane families
- Not stored in cells. Generated rapidly.
How are eicosanoids derived?
- Phospholipid–>ArAc (via phospholipase)
- ArAc–>LT (via lipoxygenase) = LT inhibs, glucocorticoids
- ArAc–>PG/TX/PC (via COX)
PH Inihib = glucocorticoids, NSAIDS
TX inhibit = NSAIDS
PC Inhibit = NSAIDS
What are leukotrienes produced by?
Mast cells
Macrophages
Neutrophils
Vascular smooth muscle cells
What are the effects of LT B4?
- Chemoattractant for neutrophils
- Promotes neutrophil adhesion
Hemorrhagic shock: Acute lung injury, AKI
What are the effects of LT C4, LT D4, and LT E4?
- Bronchoconstriction
- Vasoconstriction
- Increased vascular permeability
- Neutrophil chemoattractant
- Leukocyte adherence
What are the effects of PG E2?
- Vasodilation
- Bronchodilation
- Pyrexia
- Immunodepression by inhibiting TNF-alpha and IL-1 synthesis
- Suppresses effector function of macrophages
What are the effects of prostacyclins (PG12)?
- Produced largely by vascular endothelium
- Vasodilation
- Bronchodilation
- Inhibition of platelet aggregation
*Inhibited by glucocorticoids
What are the effects of thromboxane A2?
- Produced mainly by platelets
- Vasoconstriction
- Bronchoconstriction
- Platelet aggregation
- Potent constrictor of smooth muscle
What are kinins implicated in?
- Inflammation
- Anaphylaxis
- Septic shock
What are the principal effects of kinins?
- Vasodilation
- Increased capillary permeability
- Pain
- Tissue edema
- Stimulate production of NO: vasodilation and decreased platelet aggregation
- Activation of phospholipase and thus amplification of inflammatory response (ArAc)
- Potent bronchoconstriction
- Increase renal vasodilation: decrease renal perfusion pressurere–> decrease BP
What are the effects of histamine?
- Vasodilation
- Increased permeability
- Bronchoconstriction
What are the cytokines?
Protein messenger molecules made by immune cells to facilitate communication and orchestrate an attack
- interleukins
- IFNs
- TNFs
- CSFs
- TGFs
How do cytokines function?
Act directly on target cells and potentiate each other to amplify host response
Paracrine
Autocrine
Synergy
Pleotrophy
What are the effects of NO?
- Vasodilation
- Inhibition of platelet aggregation
- Also seem to be involved in pathophysiologic decrease in BP and SVR seen in sepsis
What is IL-1 produced by?
- Primarily monocytes and tissue macrophages (important stimulus = microbial products)
- Neutrophils
- Lymphocytes
- Endothelial cells
- Keratinocytes
What stimulates the release of IL-1?
- Microbe particles
- Ag-Ab complexes
- Ig
- C5a (opsonization)
- Other cytokines
- TGF- beta
What are the effects of IL-1?
- Fever (via effect on hypothalamus)
- Stimulation of T and B lymphocytes (promote maturation and clonal proliferation)
- Acute phase protein production and release
- Stimulates pit stress hormone release
- Myocardial depression
- Regulates skeletal muscle proteolysis in sepsis
- Potentiation of other inflammatory mediator release
- Chemoattraction of leukocytes
- Promotion of endothelial cell procoagulant effects
- Helps activate Th cells by acting as a costimulator and antigen presenting cell receptors
What is IL-6 produced by?
- Monocytes and macrophages
- Neutrophils
- Fibroblasts
Bone marrow cells
What are the effects of IL-6?
- Induces fever
- Promotes T and B cell activates: acts on proliferating B cells to promote differentiation–>plasma cells
- Stimulates acute phase protein synthesis by liver
- Stimulate antibody secretion
- Regulates hepatic response to inflammation–>CRP!!
What is TNF-alpha secreted by?
- monocytes and macrophages primarily
- lymphocytes
- mast cells
- kupffer cells
- glial cells
What stimulates TNF-alpha production?
- Endogenous and exogenous factors from microbes
- Endogenous and exogenous factors from tumors
- The most important mediator of septic shock and MODS (multiple organ dysfunction syndrome)
What are the local effects of TNF-alpha?
Leukocytes chemoattraction
- Binds to TNF receptor on cells–>activates cascade pathway–>apoptosis
- Inflam–>recruits neutrophils, monocytes, T cells, NK cells by inducing changing in vascular endothelial cell adhesion
- IFN-y potentiates TNF-alpha effects
- Overproduction–>excessive tissue destructive inflammation (ie arthritis and septic shock)
What are the effects of TNF-alpha of exaggerated systemic levels?
Acts on hypothalamus
- Fever
- Release of stress hormone (catecholamines, glucagons, cortisol)
- Myocardial depression
- Increased systemic and pulmonary vascular permeability
- Hypotension
- Lactic acidosis
- DIC
What are the effects of platelet activating factor?
Similar to histamine but longer acting
- Amplifies action of TBF-alpha and IL-1 (from platelet activation)
- Leukocyte activation, adherence, motility, chemotaxis, invasion
- Stimulates synthesis of leukotrienes
- Platelet aggregation
- Bronchoconstriction
- Increased vascular permeability
- Cardiodepression
- Hypotension
What are oxidants produced by?
Activated neutrophils among other cells
What are the effects of oxidants?
- Lipid per oxidation and membrane disruption causing cell death
- oxidative damage to DNA
- oxidative damage to amino acids and proteins
- Inhibition of ATP synthesis in both glycolytic and mitochondrial pathway
- Reduction in cellular levels of NADH
- Interference of intracellular calcium regulation
What are the effects of EPI and NE?
- Tachycardia
- Increased inotropy
- Peripheral vasoconstriction
- Increased metabolic rate
- Increased glycogenolysis and increased gluconeogenesis: hyperglycaemia
- Inhibition of insulin secretion
What are the effects of cortisol?
Glucocorticoid
- Lipolysis
- Proteolysis
- Gluconeogenesis
Primarily a catabolic steroid: inhibits lipoxygenase and COX (eicosanoid pathway)
What are the effects of glucagon?
- PEptide hormon
- Produced by pancreatic alpha cells
- Gluconeogenesis: increased glucose
