Inflammation

Question	Answer
In basic terms, what is inflammation?	It is the body's reponse to tissue damage or infection which moves immune cells and molecules to the site of infection/damage, to fight infection/limit infection, and initiate healing.
The changes in blood vessels and blood flow as a result of inflammation give rise to...?	The cardinal signs of inflammation: rubor, calor, dolor, tumor, and functio laesa.
Give a very brief overview of the inflammatory response, moving from the innate to the acquired aspects.	Tissue injury ± infection initiates the inflammatory response -> Soluble mediators (chemokines and cytokines) are released into the circulation -> These soluble mediators result in increased vasodilation and vascular permeability, as well as in adhesion of immune cells to the blood vessels -> As a result there is a chemotactic recruitment of neutrophils and monocytes -> These innate immune cells in turn recruit lymphocytes which mature and differentiate into a specific immune response if necessary -> The lymphocytes differentiate into effector cells (e.g. B plasma cells producing antibodies) and join other effector cells such as natural killer cells and phagocytes -> These resolve the infection through complement activation, cytokine release, and direct cytotoxicity.
What are PAMPs?	Pathogen-associated molecular patterns.
What are DAMPs?	Danger-associated molecular patterns.
Where are DAMPs found?	Unlike pathogen-associated molecular patterns which are found on microbial antigens, danger-associated molecular patterns are released from the host cells when they are damaged/in distress.
How might loss of function develop in inflammation? How might this lead to amputation of tissue/a limb?	So many inflammatory signals may be released in a given inflammatory response that blood vessels are blocked and limb sacrifice occurs (usually peripheries) and this is usually not reversible as a result of tissue hypoxia.
Soluble mediators of inflammation are released by damaged tissues and immune cells to recruit cells to the inflammatory response in order to fight infection and/or initiate healing of tissue damage. Which cytokines are released by macrophages? And which chemokine? Which complement proteins are activated directly by PAMPs with or without antibody? Which other vasodilating soluble mediators are involved?	Macrophages secrete cytokines TNF-α, IL-1β, and IL-6, as well as the chemokine IL-8. C3a and C5a, the anaphylotoxins, are activated directly by PAMPs and are involved in mediating inflammation. Histamine, prostaglandins, leukotrienes, and serotonin are all vasodilating soluble mediators which may be involved in an inflammatory response.
Which soluble mediators do the auxillary cells (basophils, mast cells, and platelets) release?	PAMPs stimulate basophils to release histamine, granules, and O2/lipid mediators, while C3a and C5a stimulate mast cells to release the same soluble mediators. PAMPs also stimulate platelets to release serotonin. The auxillary cells are involved as well as early response cells such as neutrophils and monocytes in order to ensure that there are enough inflammatory mediators to enhance the inflammatory response.
What are the primary effects of soluble mediators of inflammation?	They increase vascular permeability and increase the migration and activation of leukocytes.
The vascular changes at the beginning of the inflammatory response include blood vessel wall activation and increased permeability. Describe this in more detail.	The soluble mediators of inflammation cause the endothelial cells of the blood vessel walls to increase their expression of adhesins nearest to the affected tissue. These bind to integrins on the leukocyte cell membrane as they are complementary, and the leukocytes roll along the vessel wall, tether, and then adhere. Histamine and other vasoactive amines increase the vessel permeability so that the tight intercellular junctions no longer prevent the leukocytes from extravasating via diapedesis. These extravasated cells then move by chemotaxis to along chemokine gradients towards the affected tissue.
Which are the first leukocytes to be recruited in an inflammatory response?	Neutrophils! Chemotactic factors such as IL-8 are released from damaged cells/activated tissue macrophages and these create a gradient down which neutrophils can migrate, as well as activating the local blood vessel endothelium in order to facilitate extravasation and migration.
True or false: cell recruitment is enhanced by activation of tissue macrophages near small blood vessels?	True! They release cytokines and prostaglandins which encourage leukocyte adhesion to blood vessel walls and extravasation.
Are neutrophils antigen-presenting cells?	No, of the phagocytes only macrophages present antigen as well as their killing and digesting functions.
Natural killer cells and eosinophils are both cytotoxic - but to which organisms/cells?	NK cells are particularly cytotoxic to intracellular pathologies such as viruses and cancer. Eosinophils are particularly toxic to helminths.
Sometimes when there should be inflammation, it is absent, and there is a lack of resolution. List three situations in which this occurs.	1. When cancer is not recognised as cancer, for example in low dysplasia, no inflammation is triggered and it is not removed. 2) In some sterile injuries such as 'tennis elbow' the type of injury does not release PAMPs or DAMPs and therefore the inflammatory response is not triggered. 3. Organisms such as Mycobacterium tuberculosis hide in immune cells so there is no inflammation.
Absence of inflammation causes pathology, but so does excess inflammation. What is the most common disease caused by excess inflammation? What is the most fatal disease caused by excess inflammation?	Rheumatoid arthritis is the most common disease caused by excess inflammation, whereas sepsis is the most fatal - it is sometimes referred to as a 'cytokine storm'.
Which cells and soluble mediators is inflammation controlled by to avoid excess inflammation?	T regulatory cells are constitutively present in order to control inflammation to minimise tissue damage and also to end inflammation when the stimulus is removed. IL-10 and TGFβ are the soluble mediators involved in regulating inflammation.
How soon after tissue injury is there an increase in vascular diameter (vasodilation) resulting in a rise in blood volume in the area?	Within a few minutes.
How soon after tissue injury to leukocytes adhere to vascular endothelium in order to extravasate into the damaged tissue?	Within a few hours.
Can the N-formyl bacterial peptides act as chemoattractants?	Yes, the most potent for neutrophils is N-formylmethionine-leucine-phenylalanine.
Before adhesins are expressed on the endothelial wall and integrins are expressed on the neutrophil membrane in order to strongly tether the leukocyte to the vascular endothelium and facilitate extravasation, which glycoproteins are expressed on the vascular endothelium and neutrophils which allow them to form weak interactions which are easily broken by blood flow force?	Neutrophils express mucins while the vascular endothelium expresses selectins.
Other than holding bodily cells together and allowing leukocytes to extravasate, what other (immune) function do cell adhesion molecules (CAMs) have?	They serve to increase the strength of the functional interactions between T-helper cells and antigen presenting cells, between T-helper cells and B cells, and between cytotoxic T lymphocytes and target cells.
What is leukocyte adhesion deficiency (LAD)?	An autosomal recessive loss of CD18, an integral component of the integrin molecules LFA-1, CR3 and CR4 on leukocyte cell membranes. This results in recurrent and often chronic bacterial infections (though these individuals are no more or less susceptible to viral infections) and a lack of pus where one would expect to find pus. These individuals have no fewer granulocytes - in fact, they typically have greatly elevated circulating granulocytes. However, these granulocytes cannot undergo adhesion-dependent migration into sites of inflammation. Treatment is with antibiotics, though these patients have the worry of antibiotic-resistant strains of bacteria more than the healthy population, or a total bone marrow replacement from a suitable donor can be curative.

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	Created by sophietevans almost 10 years ago