IIT 5: Systemic Inflammatory Responses, Autoimmune Disease Flashcards
Define systemic inflammatory response syndrome (SARS)
Systemic consequences of localized or disseminated inflammation (systemic consequences of severe inflammation)
Define Sepsis
SIRS caused by infection.
Define bacteremia
The presence of bacteria in the bloodstream .
- low level often causes no clinical signs
- higher levels may causes sepsis or septicemia
Define septicemia
Clinically apparent severe disease as a consequence of bacteria or bacterial toxins in the blood. Bacteria + clinical disease
-term to use is sepsis instead
Define pathogenesis
- widespread distribution of the cause (eg systemic infection, anaphylaxis, etc)
- localized distribution of the cause (eg pneumonia) with systemic distribution of inflammatory mediators
What do high levels of pro-inflammatory cytokines in the bloodstream affect?
Organs distant from the site of infection, leading to fever (hypothalamus), sickness behaviour (brain), leukocytosis (bone marrow) and changes in acute phase proteins (liver)
-SIRS represents the systemic responses to high levels of pro-inflammatory cytokines in the bloodstream
What is involved in the localized inflammatory response?
- tissue damage leads to release of DAMPs (HMGB1, ATP, uric acid) OR infection leads to the presence of PAMPs (LPS, lipoteichoic acid, flagellin, viral nucleic acid) and these can activate pattern recognition receptors
- lead to inflammatory mediators like TNF, histamine, leukotrienes
- lead to leukocyte activation
- lead to endothelial activation
What are the different pattern recognition receptors?
- cell surface receptors (toll like receptors, receptors for antibody and complement)
- cytoplasmic receptors (NOD like receptors, RIG 1 like receptors)
- soluble receptors (complement system, antibody, collectins)
What does vasodilation from inflammatory mediators in localized inflammatory response lead to?
Hyperaemia and congestion -> cardinal signs of inflammation
What does vascular permeability from inflammatory mediators in localized inflammatory response lead to?
Edema, fibrin, exudation -> eliminates the threat, initiates healing
What does leukocyte activation from inflammatory mediators or pattern recognition receptors in localized inflammatory response lead to?
Diapedesis, chemotaxis, phagocytosis, killing (recruitment to tissue, adhere to vessel walls) -> eliminates the threat, initiates healing and may cause tissue damage (ischemia, free radical, protease)
What does endothelial activation from pattern recognition receptors in localized inflammatory response lead to?
increased tissue factor, decreased protein c, decreased thrombomodulin -> hyper coagulability -> thrombosis -> tissue damage (ischemia, free radical, protease)
What is involved in systemic inflammatory response syndrome and sepsis?
- tissue damage leads to release of DAMPs (HMGB1, ATP, uric acid) OR infection leads to the presence of PAMPs (LPS, lipoteichoic acid, flagellin, viral nucleic acid) and these can activate pattern recognition receptors
- lead to inflammatory mediators like TNF, histamine, leukotrienes
- lead to leukocyte activation
- lead to endothelial activation
What is the effect of the acute phase response from inflammatory mediators in systemic inflammatory response?
- inflammatory mediators circulate through body and blood, effect on distant tissues
- fever, depression, inappetence, leukocytosis, acute phase proteins
What is the effect of inflammatory mediators on vasodilation in systemic inflammatory response?
Vasodilation occurs throughout body and causes systemic hypotension (shock), which leads to increased heart rate and rest rate and tissue damage in kidney, liver, lung mostly
What is the effect of inflammatory mediators on vascular permeability in systemic inflammatory response?
Increased vascular permeability leads to tissue edema, leads to tissue damage
What is the effect of inflammatory mediators and pattern recognition receptors on leukocyte activation in systemic inflammatory response?
-oxygen and nitrogen radicles, proteases, tissue damage
What is the effect of pattern recognition receptors on endothelial activation in systemic inflammatory response?
-endothelial activation (increased tissue factor, decreased protein C, decreased thrombomodulin) leads to increased coagulation can lead to disseminated intravascular coagulation, can cause tissue damage and consumptive coagulopathy
What is an acute phase response?
Systemic adaptive responses to severe inflammation.
What is the acute phase response largely driven by?
- the cytokines interleukin 6 (IL-6), IL-1
- TNF
- In mild inflammatory diseases, these cytokines are only active at the site of inflammation, and plasma cytokine binding proteins or cytokine inhibitors neutralize any cytokine that leaks into circulation
What are the systemic changes in pathologic processes during disease (acute phase response)?
- fever
- anorexia, depression
- cachexia - catabolic state, lose weight/muscle mass
- leukocytosis
- cortisol secretion
What are acute phase proteins?
Help identify animals in the acute stages of inflammatory disease. These are the proteins produced in the liver whose levels in plasma are changed by inflammation.
- eg haptoglobin, fibrinogen, C reactive protein
- a shift away from non-essential functions to deal with the imminent threat
- In acute phase, the liver decreases the production of negative acute phase proteins and increases the production of positive ones
What does haptoglobin do?
- acute phase protein
- binds hemoglobin, making the iron in hemoglobin unavailable to most bacterial pathogens
What does c reactive protein do?
- acute phase protein
- binds bacterial pathogens, reduces oxidative burst in neutrophils and binds to damaged tissues
What are come functions of positive acute phase proteins?
These are helpful things.
- control of pathogens to deal with bacterial infections
- quell inflammation (reduce systemic inflammatory response)
- minimize tissue damage
What happens in systemic inflammatory response syndrome?
The inflammatory stimulus acts on the macrophage, inflammatory mediators are produced like IL6, IL1, TNF alpha
- produce PGE2 which acts on hypothalamus to cause fever
- act on behaviour to cause malaise, anorexia
- act on marrow for leukocytosis (release NPs quickly, increase production)
- act on liver to make acute phase proteins
- these things have short half life, cytokine inhibitors in serum
What are the different categories of SIRS?
- can either be infectious (sepsis) or non-infectious (like widespread tissue trauma)
- Infectious can be localized -> cytokinemia (eg bacteria only in lung tissue, cytokines throughout body for systemic inflammation) or disseminated: bacteremia (septicemia) where bacteria is throughout the body
