03: Phenotypic Presentation of Systemic Inflammation

Question 1

Benefits of systemic inflammation

Answer 1

• Defense against infection
• Cancer surveillance
• Hemostasis/homeostasis after acute tissue damage/injury
• Wound healing

Question 2

For systemic inflammatory response, what are the major cytokines, what are their targets, and what are the outcomes?

Answer 2

Cytokines: TNF, IL-6, IL-1, IFN, lymphotoxin, chemokines

Targets:

• Bone marrow: leukocytosis, thrombocytosis
• CNS: fever, somnolence, lethargy
• Liver: synthesis of APR, complement, hepcidin, triglycerides; ↓glycogenesis, albumin synthesis
• Muscle: ↓glucose uptake, sarcopenia
• Adipose: lypolysis, FFA release, adipokines
• Blood vessels: endothelium primed for leukocyte transmigration, plaque rupture, atherogenesis
• RES: migration of dendritic cells to lymph nodes

Question 3

What are acute phase reactants (APRs)?

Answer 3

• Class of proteins whose plasma concentrations ↑in response to cytokines and other extra-cellular signals
• While cytokines circulate in v. low concentrations, APRs circulate in high concentrations
• While cytokines have narrow range of variability, APRs can inrease 10-100 fold on induction

Question 4

Induction of APRs

Answer 4

• Activated leukocytes (macrophages) secrete cytokines (**TNF, IL-1 **–> IL-6) in response to injury
• Liver responds (mainly to IL-6) by producing large number of APRs:
  
  • complement
  • CRP
  • fibrinogen
  • serum amyloid A
  • haptoglobin
  • ferritin
  • mannose binding lectin

Question 5

C-reactive protein (CRP)

Answer 5

• An acute phase reactant
• Synthesized by hepatocytes under cytokine stimulation
• Fixes complement
• Binds to macrophages to induce inflammatory cytokines
• Binds endothelial cells to expose tissue factor

Question 6

Erythrocyte sedimentation rate (ESR)

Answer 6

• Indirect measure of APRs
• Increase w/:
  
  • Age, gender
  • Temperature of sample
  • Smoking
  • Increased plasma proteins (Igs, fibrinogen, etc.)
  • Microcytic anemia or variable RBC size
  • Increased plasma viscosity
• Decrease w/:
  
  • Polycythemia
  • Extreme leukocytosis
  • Sickle cell anemia

Question 7

What is the mechanism of fever during infection?

Answer 7

• Exogenous pyrogens (microbes and microbe products, toxins) stimulate leukocytes to produce endogenous pyrogens (monocytes/macrophages, neutrophils, IL-1, TNF, lymphotoxin, interferons, IL-6)
• Endogenous pyrogens circulate, signal CNS –> prostaglandin (PGE2) synthesis
• PGE2 rasies thermostatic set point of hypothalamus

Question 8

What is the mechanism of anemia of inflammation?

Answer 8

• Iron, erythropoietin and RBC survival affected:
  
  • ↓circulating iron and iron binding capacity
  • nl/↑ whole body iron stores
  • blunted response to endogenous and exogenous erythropoeitin
  • ↓RBC lifespan
• Hepcidin: negative regulator of iron homeostasis via ferroportin inactivation (absence –> iron overload); regulates release of iron from liver and macrophages
  
  • During inflammation, IL-6 via NF-KB promotes hepcidin production –> ↓iron release into circulation
  • Treatment w/ IL-6 inhibitor normalizes hemoglobin

NB: supplying exogenous Fe or erythropoietin do NOT resolve the anemia

Question 9

What are the mechanisms of cachexia?

Answer 9

• Multifactorial:
  
  • Cytokine-driven (TNF, IL-1, IL-6)
  • Reduced physical activity
  • Effects of altered hormone signaling/insulin?
• Chronic exposure of cells to TNF –> dose-dependent degradation in total protein content (catabolized by inflammatory cytokines)
• Other mechanisms:
  
  • Myocyte apoptosis
  • ↓ muscle quality by infiltrating fat
  • ↓ levels/resistance to growth factors
  • ↓ levels/resistance to androgens
  • proteolysis due to TNF-dependent ↑ROS

Question 10

What are the mechanisms of systemic inflammation?

Answer 10

• Acute phase reactants
• Fever
• Anemia
• Cachexia
• Energy metabolism
• Atherogenesis/atherothrombosis

Question 11

What are the mechanisms of energy metabolism?

Answer 11

• Cytokines facilitate release of glucose and FFA into circulation (essential sources of energy during infx, acute injury and healing)
• Chronic exposure to cytokines –> DM, insulin resistance, atherogenic lipid profile, atherogenesis
• TNF-a acts on:
  
  • Adipose: via p55 receptor –> lypolysis, FFA release
  • Liver: ↑hepatic glucose production, ↑triglyceride production, ↑VLDL prodcution, ↓VLDL clearance
  • Skeletal muscle: via p55 –> altered (↓) insulin-signaled glucose uptake

Question 12

What is pro-inflammatory HDL?

Answer 12

• **Apo A-1 **in HDL promotes reverse cholesterol process
• Inflammation –> accumulated oxidants in HDL –> inactivated Apo A-1 –> inhibited reverse cholesterol process
• Facilitiates formation of oxidized LDL

Question 13

What are the mechanisms of atherogenesis/thrombosis?

Answer 13

• Endothelial dysfunction –> early stage atherosclerosis
• Atheroma (degenerated artery wall) formation –> potentiated by other CVD risk factors
• Plaque instability & rupture –> cinical events (MI)
• Inflammatory cytokines have direct/indirect effects on vasculature:
  
  • upreg of vascular adhesion molecules
  • macrophage activation & recruitment
  • upreg of other pro-inflammatory cytokines
  • vascular matrix remodeling (MMPs, TIMPs)
  • regulation of apoptosis in vascular SMCs
  • induction of pro-coagulant state
  • modulation of glucose metabolism
  • modulation of fat/lipid metabolism
  • antagonism of anti-inflammatory pathway

NB: eliminating TNF reduces atherosclerotic burden