Cellular Events in Acute Inflammation, Chemical Mediators and Chronic Inflammation

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Conran, SEM 3 ROSSU

List the order of Cellular events that lead to transmigration:

Margination, Rolling, Adhesion, Transmigration

What types of adhesion molecules regulate adhesion?

Integrins and Selectins

What does P-Selectin do? What receptor does it work on?

It mediates Rolling only (Neut., Monos., Lymphs.) and they act on the Sialyl-Lewis X/ PSGL-1 receptor.

What does E-Selectin Do?

It mediates both rolling and adhEsion. It works on Sialyl-Lewis, ESL-1, and PSGL-1 receptors.

What does ICAM-1 do?

It mediates adhesion, arrest, and transmigration of all leukocytes. It works on the Beta-Integrin receptors.

What does VCAM-1 do?

It mediates adhesion of Eos,, Monos, and Lymphs. It works on the Alpha-4-Beta-1 Integrin Receptors.

What adhesion molecules mediate transmigration?

PECAM-1/CD99

Describe the redistribution of P-Selectin and its role in adhesion:

Endothelial Cells contain Weible-Palade Bodies which are storage granules. Upon stimulate by Histamine or Thrombin, the endothelial cell will push these bodies to the periphery facing the lumen. These will release P-Selectin which mediate rolling only.

Describe the induction of endothelial adhesion molecules E-Selectin; ICAM-1:

When a neutrophil begins to adhere to the endothelial cell, it begins to secrete IL-1and TNF which will induct the secretion of Adhesion Molecules E-Selectin and ICAM-1. Both of these mediate adhesion.

What do Chemokines, IL-8 , and PAF do in regards to integrins?

They increase the avidity of integrins.

Explain how an Inflammatory Stimulus will activate Inflammation via a G-Protein Mediated Stimulus:

The G-Proteins activate Phospholipase C which will do 3 major things: 1. it will increase ICF Calcium to increase adhesion molecule expression, cause degranulation, increase cytokine assembly and increase oxidative burst. 2. It will activate Protein Kinase C which will activate the release of Cytokines, increase oxidative burst, and increase arachidonic acid. 3. it will directly increase Arachidonic Acid

Do G-Protein Coupled Receptors recognize Microbes?

They can bind neutrophils and macrophages. In addition they recognize short bacterial peptides containing N-formylmethionyl residues.

What does Superoxide Dismutase create?

Hydrogen Peroxide from the Superoxide Radical

Where can the H202 from the Superoxide Dismutase reaction go to?

Into the Heiber-Weis or Fenton Reactions to create the hydroxyl radical

What does the Myeloperoxidase Reaction yield?

Hypochlorous Acid

Give examples in which a patient would acquire a deficiency in chemotaxis:

Thermal Injury, Diabetes, Sepsis

Give examples in which a patient would acquire a deficiency in adhesion:

Diabetes, Alcoholism, and Hemodialysis

Give examples in which a patient would acquire a deficiency in phagocytosis:

Diabetes, Anemia, Sepsis, and Leukemia

What are the preformed mediators of inflammation?

Histamine, Serotonin, and Lysosomal Enzymes

What are the Newly Synthesized mediators of inflammation?

Prostaglandins, Leukotrienes, PAF, activated O2species, NO, and cytokines

What are the 3 sources of plasma proteases?

The Complement System, Kinin System, and the Clotting System

Describe the Complement System's role in mediating inflammation:

All 3 complement pathways lead to C3b being deposited on the microbe. There are 3 effector functions that come from this: 1. C3a and C5a will recruit and activate WBCs to destroy the Microbes. 2. Phagocyte will recognize the C3b on the microbe so it can opsonize and destroy the microbe. 3. The MAC is formed and lyse the microbe.

What complements act on mast cells to cause degranulation?

C3, C4, C5

Describe the Kinin's System's role in mediating inflammation:

High Molecular Weight Kininogen will activate Factor 12 or Hageman Factor. This will activate PreKallikrein into Kallikrein. Together Killikrein and High Molecular Weight Kininogen will activate Bradykinin. This is will cause increase vascular permeability and pain.

How does the Clotting Cascade, The Clotting System, and the Kinin Cascade Interact?

Kalikrein will activate Hageman Factor as well as act in the Fibrinolytic system to activate Plasmin. The Hageman Factor will lead to the Kinin Cascade as well as the Clotting Cascade. Plasmin will activate the Complement Cascade leading to an increase in C3a while breaking down the product of the clotting cascade (Fibrin).

Describe the Cyclooxygenase Pathway in general:

Cell Membrane Phospholipids are made into arachadonic acid via phospholipase. Cyclooxygenase works on that to create prostaglandins.

Describe the Lipoxygenase Pathway and the creation of a major chemotactic factor from this pathway:

Cell Membrane Phospholipids are made into Arachadonic Acid via Phospholipase. 5-Lipoxygenase works on that to create 5-HPETE which will give rise to the major chemotactic factor LTB4.

What do steroids inhibit?

Phospholipases

What is PAF?

Platelet Activating Factor. It leads to increased vascular permeability. It causes Leukocyte aggregation, adhesion, activation and chemotaxis. It activates platelets and stimulates other mediators therein.

What releases PAF?

Mast Cells/Basophils, Neutrophils, Monocytes/Macrophages, Endothelium, and Platelets.

How does histamine act on inflammation?

It causes vasodilation, increased vascular permability, and endothelial activity

How does Serotonin act on inflammation?

It causes vasodilation, vascular permeability

How do Prostaglandins act on inflammation?

It causes vasodilation, pain, and fever

How do Leukotrienes act on inflammation?

It causes vascular permeability, chemotaxis, adhesion, and activation of WBCs.

How does PAF affect inflammation?

It causes vasodilation, increased permeability, adhesion, chemotaxis, degranulation, and oxidative burst.

How does ROS affect inflammation?

It kills microbes and can cause tissue damage

How does NO affect inflammation?

It increases vascular smooth muscle relaxation and can kill microbes.

How do Cytokines affect inflammation?

They can cause local endothelial activation of adhesion, fever, pain, anorexia, hypotension, and shock.

How do Chemokines affect inflammation?

They act on chemotaxis and active WBCs

Where are the Kinins, Proteases, and Compelment Products C3a,C4a, and C5a all produced?

The Liver!

What happens to tissue in scaring?

It contracts

What is the definition of chronic inflammation?

Inflammation which persists for prolonged periods of time and lasts for weeks, months, or years and has little fluid component.

Give an example of how chronic inflammation can occur without an acute phase:

Viral Diseases in which there is an insidious onset of the illness

Describe the Morphology that occurs in Chronic Inflammation:

There is an infiltration of mononuclear cells such as macrophages, lymphocytes, plasma cells, eosinophils, and mast cells. Fibroblasts begin to proliferate as well as blood vessels due to increased angiognesis and fibrosis. Collagen is deposited (fibrosis) and tissue is destroyed.

What is the most important mediator of chronic inflammation?

Macrophages

What is the half-life of circulating monocytes?

1 day

How long does it take for chemotactic factors to cause monocytes to emigrate to the site of the injury?

Within the first 24-48 hours

What happens to monocytes when they reach extravascular tissue?

They transform into macrophages

What happens to macrophages when they are activated?

They grow. They increase in lysosomal enzyme content. Their metabolism increases. Their killing capacity increases.

What are the general macrophage activation signals?

Cytokines secreted and synthesized by T-Lymphocytes (IFN-y), bacterial endotoxin, various mediators produced by acute inflammation, and extracellular matrix proteins such as fibronectin.

What do Activated Macrophages secrete?

Acid and Neutral Proteases, Proinflammatory Substances, Plasminogen Activator, and Complement Components. They will also secrete coagulation factors.

Which Complement Components do Macrophages release?

C1 to C5 and properdin

What coagulation factors do macrophages secrete?

Factor 5 and Factor 7, and tissue factor

Which Reactive Oxygen Species do macrophages secrete?

NO

What Cytokines to Macrophages release?

IL-1 and TNF. It will also secrete growth factors that cause the proliferation of smooth muscle cells and fibroblasts

Which cytokines can induce macrophages to fuse into multinucleated giant cells?

IL-4 and IFN-y

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