Inflammation/Cytokines Flashcards
Inflammation definition:
–Inflammation is the reaction of living tissue and its microcirculation to pathogenic insult; –Generation of inflammatory mediators; –Movement of fluid and leukocytes from blood into extravascular tissues.
Inflammation Purpose:
–Localize or eliminate the cause of the pathogenic insult; –Limit tissue injury; –Remove or repair injured tissue components; –Restoration of normal physiology.
Acute inflammation:
–Immediate reaction to tissue injury –Rapid onset –Innate immunity –Neutrophil cell predominance –Duration hours to weeks –Prominent vascular response
Chronic inflammation:
–Persistent reaction to tissue injury –Slow response –Cell-mediated immunity –Mononuclear cell predominance (lymphocytes, plasma cells, monocytes) –Duration weeks to years –Less prominent vascular response
Causes of acute inflammation:
-Microbial infections -Tissue necrosis -Physical agents -Chemical irritants -Immune-mediated hypersensitivity
Causes of chronic inflammation:
-Persistent tissue injury and acute inflammation -Microorganisms resistant to phagocytosis or intracellular killing (Mycobacteria, viruses, fungi, some parasites) -Foreign bodies -Autoimmune disorders -Primary granulomatous diseases
What is shown in this image?
This is an image of a healthy lung
What is shown in this image?
This is a slide of fatal acute pneumonia, where neutrophils fill alveoli/lungs.
Fatal Acute Pneumonia:
Pneumonia is inflammation and consolidation of pulmonary parenchyma.
Bronchopneumonia remains a common cause of death.
Acute inflammatory disease is a significant cause of morbidity and mortality.
Outcomes of inflammation:
- Localizes or eliminates the cause of injury;
- Removes injured tissue components;
- Leads to repair.
- Inflammation is usually beneficial but it can definitely cause morbidity and mortality.
Edema is an important aspect of inflammatory response for vasoactive mediators. What are two main sources?
- Plasma derived
- Cell derived
Plasma-derived sources of edema:
Hangeman factor activation (stimulates clotting fibrinolytic system –> fibrin split products; stimulates Kallikrein-kinin system –>kinins).
Complement system activation (Mediators = C3a and C5a)
Cell-derived sources of edema:
- Mast cell/basophil degranulation (mediator = histamine),
- Platelets (mediator = serotonin)
- Inflammatory cells (mediators = platelet-activating factor, prostaglandins, leukotrienes)
- Endothelium (mediators = nitric oxide, platelet-activating factor, prostaglandins)
Vasoactive mediators of edema result in increased ________, which results in edema.
vascular permeability
Chemotaxis:
Directed cell migration
Mechanism of phagocytosis and cell killing:
Neutrophils, monocytes, and macrophages do this.
Neutrophil is in blood vessel and respond to chemotaxic signals to reach bacteria. It will bind to the bacteria, because it has been coated with complement C3b and potentially also have antibodies recognizing it, which provides a handle for the neutrophil to hold on (can perform task without these, but they give it a jump start). Bacteria is labeled and marked for destruction. Neutrophil takes it in and forms a phagosome. Granules assemble around phagosome. Neutrophil generates respiratory burst. Generate oxygen species, degrade bacteria using lysosome, iron. Make hydrogen peroxide to try to degrade them.
Phagocytic cell oxidative burst purpose:
Purpose is to generate hypochlorous acid and hydrogen peroxide. This process is important and organized.
Events begin with molecular oxygen. Make superoxide anion, which has a short half-life. It re-stabilizes and then makes hydrogen peroxide, which can make hydroxyl radical and bleach, and this continues the degradation of the microorganism.
Order of events in Phagocytic Cell Respiratory Oxidative Burst:
- Molecular oxygen reduced by NADPH oxidase produces superoxide anion.
- Generation of hydrogen peroxide via superoxide dismutase (SOD).
(Preliminary reactive species responsible for killing ingested microorganisms are generated from superoxide and hydrogen peroxide in a series of reactions)
- Hydroxyl radical attacks DNA.
- Hypochlorous acid generated with myeloperoxidase catalyst. HOCl has many toxic effects.
Chronic granulomatous disease (CGD):
An inherited disorder of phagocytic cells, results from an inability of phagocytes to produce bactericidal superoxide anions (O2-). CGD is caused by a defect in the nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) oxidase enzyme of phagocytes. Phagocytic cells are unable to generate hydrogen peroxide (H2O2) and superoxide (O2-), both needed for microbial killing. Phagocytic cells are unable to kill catalase-positive microorganisms, that is, those that can break down H2O2. By contrast, catalase-negative organisms produce H2O2 themselves and it gets released into the granules of the CGD phagocytic cells and reacts with myeloperoxidase to produce the toxic substances that can then kill the bacteria.
How do e.g. neutrophils get to the site of infection?
Cells migrate down blood vessel. At the site of infection, Macrophages and dendritic cells show up and try to engulf the organism and recruit more neutrophils to leave blood vessel. Send out cytokines and inflame blood vessel right at the site of infection. In the inflamed region of the vessel, integrins and instructions are upregulated, telling the neutrophil to stop at this site. It can then respond to the macrophage signals that are sending out chemokines and creating a gradient to help tell the neutrophil to crawl through endothelial cells and swim to site of infection.
What are the differences between fibrinous exudate and fibrosis?
Fibrinous exudate - fluid filled with fibrin. Actively have fluid at the site of infection with fibrous components in it.
Fibrosis - scar tissue (end product).
What are the differences between granulation tissue and granulonatous inflammation?
Granulomatous inflammation is a special form of chronic inflammation characterized by granuloma formation. A granuloma is a dense accumulation of predominantly mononuclear phagocytes, typically surrounded by a collar of lymphocytes.
What are cytokines?
Cytokines are low molecular weight, soluble proteins that are produced in response to an antigen and function as chemical messengers for regulating the innate and adaptive immune systems.
-They are produced by virtually all cells involved in innate and adaptive immunity, but especially by T helper (TH) lymphocytes.
Cytokines are pleitropic, meaning:
that a particular cytokine can act on a number of different types of cells rather than a single cell type.
Cytokines are redundant, meaning:
A number of different cytokines can carry out the same function.
Cytokines are multifunctional, meaning:
The same cytokine is able to regulate a number of different functions.
Some cytokines are antagonistic:
One cytokine stimulates a particular defense function while another cytokine inhibits that function.
Some cytokines are synergistic, meaning:
Two different cytokines have a greater effect in combination than either of the two would by themselves.
Four functional categories of cytokines:
- Cytokines that regulate innate immune responses,
- ones that regulate adaptive immune responses,
- ones known as chemokines that promote directed cell migation,
- cytokines that stimulate hematopoiesis
Important cyokines involved in innate immunity’s acute-phase response:
Tumor necrosis factor (TNF), IL-1, IFN-gamma, IL-6
Principal cell sources of TNF:
Macrophages, T cells
Pricipal cellular targets and biologic effects of TNF:
Endothelial cells: activation (inflammation, coagulation),
Neutrophils: activation,
Hypothalamus: fever,
Liver: synthesis of acute-phase proteins,
Muscle, fat: catabolism (cachexia),
Many cells types: apoptosis
[component of innate immunity]
Principal cell sources of IL-1:
Macrophages, endothelial cells, some epithelial cells
Principal cellular targets and biologic effects of IL-1:
Endothelial cells: activation (inflammation, coagulation),
Hypothalamus: fever,
Liver: synthesis of acute phase proteins,
T-cells: T-helper-17 differentiation
[component of innate immunity]
