Chemical Mediators of Inflammation Flashcards
Is histamine (H) cellular-derived or plasma protein-derived?
It is a cell derived mediator
Name two vasoactive amines.
- Histamine
2. Serotonin
What are the effects of histamine?
- Arterial dilation
2. Endothelial contraction
Name three cells that release histamine
- Mast cells
- Basophils
- Platelets
What inactivates histaminase?
Histaminase
Name 6 things that initiate the release of histamine from mast cells.
- Physical causes (mechanical or temperature)
- Immune- binding of IgE
- Compliment (C3a, C5a)
- Histamine releasing proteins (from leukocytes)
- Neuropeptides
- Cytokines (IL-1, IL-8)
What is the effect of serotonin on vessels?
Vasoconstriction to aid in clotting
What cells in the blood contain serotonin?
Platelets contain serotonin granules
Where is arachidonic acid (AA) derived from?
AA is derived from cell membrane phospholipids and is transformed into a number of compounds that mediate inflammation and hemostasis
Name four sources of arachidonic acid (AA).
- Leukocytes
- Mast cells
- Endothelium
- Platelets
What two things can inactive arachidonic acid (AA)?
- Spontaneous decay
2. Enzymes
AA metabolites are formed by two main pathways.
1. Cyclooxygenase
2. Lipoxygenase
What does each pathway produce?
- Cyclooxygenase- prostaglandins and thromoboxanes
2. Lipoxygenase- Leukotrienes and lipoxins
What drugs interact with AA metabolism?
NSAIDs block cyclooxygenase
Glucocorticoids block phopholipase A2 (which shuts down the whole AA pathway)
Prostaglandins are produced by what pathway?
Cyclooxygenase
What are the effects of prostaglandins?
They contribute to symptoms of pain and fever
What two compounds are produced by the lipooxygenase pathway?
- Leukotrienes
2. Lipoxins
What are the functions of leukotrienes?
Mediate specific functions in inflammation. Ex. Chemotactic for neutrophils
What compound is generated by leukocytes as they enter tissue?
Lipoxins
What are the functions of lipoxin?
They antagonize leukotrienes and are anti-inflammatory. Ex. Inhibit neutrophil chemotaxis
Name three functions of platelet-activating factor.
- Platelet aggregation
- Vasodilation
- Vascular permeability
- Bronchoconstriction
How are platelet-activating factors produced?
Similarly to AA: phospholipase A2 cleaves lipids from cell membranes
Are cytokines part of the innate or adaptive immune system?
Both
What are the functions of TNF and IL-1?
They cause endothelial activation (leukocyte binding and recruitment)
What are some systemic effects of TNF and IL-1?
- Fever
2. Acute phase protein synthesis
What produces TNF and IL-1?
Macrophages, mast cells, and endothelial cells
What stimulates macrophages, mast cells, and endothelial cells to produce TNF and IL-1?
Presence of microbial products, immune complexes and T cell mediators
Chemokines are small proteins separated into two groups based on structure. What are the two groups?
- CXC
2. CC
What is the primary function of chemokines?
Chemotaxis, but also activates leukocytes.
What is the function of CXC?
Chemotactic for neutrophils (IL-8)
What is the function of CC?
Chemotactic for a variety of cells (e.g. eotaxin for eosinophils)
What is the function of IFN-gamma?
Stimulates classical macrophage activation
What is the function of IL-12?
Stimulate the growth and function of T cells
What cell(s) release reactive oxygen species (ROS)?
Neutrophils and macrophages
Name three forms of reactive oxygen species (ROS).
- *O2- (NADPH oxidase pathway)
- *OH
- HOCL* (Myeloperoxidase in neutrophils)
What enzyme protects host cells from reactive oxygen species?
Superoxide dismutase
What are four functions of NO?
- Free radical that kills microbes
- Vasodilation
- Antagonizes platelet activation
- Reduces leukocyte recruitment
What is NO produced from?
L-arginine
What enzyme converts L-arginine to NO?
Nitric oxide synthase (NOS)
From what cells is type II, inducible NOS produced?
Macrophages and endothelial cells.
What induces macrophages and endothelial cells to make Type II, inducible NOS?
IL-1, TNF, INF-gamma and bacterial endotoxin. This NO is related to inflammation
From what cell is type III, endothelial NOS produced?
….Endothelial. It is constitutively expressed in endothelial cells
What cells produce lysosomal enzymes?
- Neutrophils- azurophil granules
2. Monocytes- granules
What is the function of lysosomal enzymes?
To kill microbes and digest ingested materials, but it can also damage host tissue
In what environment is acid protease activated?
Neutral protease?
Within the phagolysosome (low pH)
Activated outside the cell (neutral pH)
What mitigates damage of the host tissue from proteases?
Protease inhibitors
Name two protease inhibitors and their functions.
- Alpha-1-antitypsin: neutrophil elastase inhibitor
2. Alpha-2-Macroglobulin: Inhibits a large variety of proteinases
Are the granules within the neutrophil all the same??
No!! They are different and have different functions
What is the function of neuropeptides?
They initiate inflammation particularly active in vascular tone and permeability
What organs are neuropeptides particularly active?
The lung and the GI
What is substance P?
A neuropeptide that is 11 amino acids long.
- Secreted by nerves and inflammatory cells
- binds the neurokinin-1 receptor
- generates proinflammatory effects in immune and epithelial cells
Is complement plasma protein derived or cell derived?
Plasma protein-derived mediator
Is compliment involved in an inflammatory or immune process?
Both
What does compliment do to vasculature and leukocytes?
Causes increased vascular permeability and leukocyte chemotaxis
How is compliment activated?
Proteolysis
What enzyme converts C3 to C3a and C3b?
C3 Convertase
What three separate pathways lead to C3 convertase formation?
- Classical
- Alternative
- Lectin
What is the function of C3a and C5a?
They increase vascular permeability and stim mast cells to release histamin
What is the function of C5a?
Activates the lipogenous pathway for AA metabolism
What is the function of C5a, C4a, C3a?
Activate leukocytes increasing their endothelial adhesion. Also chemotactic agents for neutophils, eopinophils, basophils, and monocytes
What is the function of C3b?
Acts as opsonin for enhanced phagocytosis
What is the function of MAC?
Essentially multiple C9 proteins (formed by 5b-C9). Creates pores that violate the membranes of some bacteria
What is the function of C1 inhibitor?
Blocks activation of C1
What is the function of decay-accelerating factor (DAF) and factor H?
Limit C3/C5 convertase formation
Where are inhibitors of complement found?
- Free within the plasma
2. Associated with cells protect host tissue
What are three functions of Factor XII (Hageman factor)?
- Activates the kinin system
- Stimulates the clotting cascade, including several other factors that impact inflammation
- Whenever clotting system is activated, so the fibrinolytic system
What is the function of kenin system?
- Eventually becomes bradykinin which causes increased vascular permeability, vascular dilation and pain
- Intermediate product Kallikrein is chemotactic and activates Factor XII
What is a function of Factor Xa?
Leads to vascular permeability
What are three functions of thrombin in inflammation?
- Binds to protease activated receptors on endothelial cells, activating them
- Cleaves fibrinogen creating fibrinopeptides which increase vascular permeability and are chemotactic
- Cleaves compliment factor 5 forming factor 5a
What role does the fibrinolytic system play in inflammation?
Releases active inflammatory mediators resulting in vascular permeability, dilation and C3a formation
What antagonizes leukotrienes?
Lipoxins
What antagonizes complement?
Compliment regulatory proteins (C1 Inhibitor)
What antagonizes the activation of macrophages?
IL-10
What is the function of TGF-beta?
Promotes fibrosis and is anti-inflammatory
