Week 3: Inflammation Flashcards
Allostatic Load
Is an index of the cumulative wear and tear on the body caused by repeated activation of multiple physiologic systems over time in response to environmental demands in an effort to maintain internal equilibrium
Identify the cytokines involved in the vascular and cellular responses of the inflammatory process including vasodilation, vascular permeability, pain, systemic manifestations of inflammation, repair and healing and phagocytosis
Cytokine are a family of intercellular-signaling molecules that bind to specific cell receptors and regulate innate or adaptive immunity. They can be pro-inflammatory or anti-inflammatory, synergistic or antagonistic, pleiotropic (same molecule can have many different biologic activities), and include interleukins, interferons, and tumor necrosis factor (TNF)
Vascular Response
Vascular Response: after initiation by the plasma protein system, mast cells, tissue macrophages, and dendritic cells, the inflammatory response has an almost immediate effect on the blood vessels.
1. Hemostasis (coagulation): injury to blood vessels initiates the clotting cascade and activates platelets
2. Vasodilation: arteriole and venule dilation increase the diameter of blood vessels, increasing the volume of blood to the injured area - contributes to redness and warmth in the area
3. Increased vascular permeability: blood vessels become more porous resulting in exudation and edema of the area
4. Leukocyte cell adhesion: leukocytes adhere to the inner walls of vessels
Together, these vascular changes deliver leukocytes (particularly neutrophils and macrophages), plasma proteins, and other biochemical mediators to the site of injury
Explain the role of the three plasma protein systems of inflammation
Protein systems that provide a biochemical barrier against invading pathogens, activated early in inflammation.
1. Complement system
2. Clotting system
3. Kinin system
The activation of the first component of a system results in sequential activation of other components, this is called a cascade.
State the five cardinal signs of acute inflammation and describe the physiologic mechanisms involved
- Redness (vasodilation - increased blood flow)
- Heat (vasodilation - increased blood flow)
- Swelling (increased capillary permeability)
- Pain (stimulation of nerve endings)
- Loss of function
Differentiate between acute and chronic inflammation
Chronic inflammation is inflammation that lasts 2 weeks or longer and is often related to an unsuccessful acute inflammatory response. Characteristics include:
- dense infiltration of lymphocytes and macrophages
- granuloma formation
- epithelioid cell formation
- giant cell formation
Explain the pathophysiology that results in local and system manifestations of inflammations
Local manifestations: result from vascular changes and corresponding leakage of circulating components into the tissue - functions to dilute toxins, carry plasma proteins and leukocytes to the injury site, carry bacterial toxins and debris away from the site, initiates healing
Explain the role of gut microbiome and dysfunction in the pathogenesis of inflammation
The microbiome interacts with the body in a beneficial way to foster healthy defense systems:
- induces protective immune responses & supports immune tolerance of innocuous micro-organisms
- synthesizes metabolites
- releases antibacterial substances
- competes with pathogens for nutrients
- blocks attachment of the pathogens to the epithelium
- produces enzymes that aid digestion of fatty acids & polysaccharides
Some members of the normal bacterial microbiome are opportunistic pathogens - that is, they are harmless under normal conditions but can cause disease in immunocompromised individuals who lack the usual defense mechanisms.
Discuss the common laboratory tests used to help diagnose inflammation
An increase in the total number of WBCs in combination with an abnormal differential count suggests there may be an ongoing infection and/or inflammatory response.
Hepatic synthesis of many plasma proteins is increased during inflammation
- measurement of acute-phase reactants
- fibrinogen
- ESR “sed rate”
- C-reactive protein (CRP levels from 1 mg/dL to 10 mg/dL are thought to be a moderate increase. CRP Levels greater than 10 mg/dL are considered a marked increase.)
The normal number of WBCs in the blood is 4,500 to 11,000 WBCs per microlite
Describe Innate Barriers
Form the first line of defense at the body’s surfaces. These barriers can be physical, mechanical, and biochemical.
Define Inflammation
A response that is meant to both protect against injury and illness and also support healing.
- Occurs in tissues with blood supply (vascularized)
- Rapidly initiated
- Involves activities of cellular and chemical and vascular components
- Non-specific - takes place in approximately the same way regardless of the type of stimulus or past occurences
- No memory cells
Cellular Response
- Neutrophils
- Macrophages
- Phagocytosis
Complement System
Intensifies, activates or collaborates with other components of the inflammatory response - “complements” them. When activated, initiates proteolytic steps (breakdown of proteins into smaller substances) these can destroy pathogens directly or enhance the activity of other components to kill pathogens.
Anaphylatoxin activity resulting in mast cell degranulation, leukocyte chemotaxis, opsonization, cell lysis
Activation of the complement system can be accomplished in three different pathways, all of which activate the protein C3:
1. Classical pathway
2. Lectin pathway
3. Alternate pathway
Classical Pathway
Part of the Complement system and is activated by antibodies (adaptive immune system) bound to their specific targets (antigen). Antibodies of the acquired immune response can use the complement system to kill bacteria and activate inflammation
Lectin Pathway
Part of the Complement system; activated by mannose-containing bacterial carbohydrates
Alternate Pathway
Part of the Complement system; activated by gram-negative bacterial and fungal cell wall polysaccharides
What are the four functions of C3s?
- Opsonization
- Anaphylatoxin activity resulting mast cell degranulation
- Leukocyte chemotaxis
- Cell lysis
Clotting System
When these plasma proteins are activated sequentially, they form a fibrous mesh that contains platelets at the site of injury/inflammation. The main substance and end product of coagulation is fibrin (an insoluble protein).
- prevents the spread of infection
- traps microorganisms & foreign bodies at the site of inflammation so inflammatory cells can access and attack them
- Forms a clot that stops bleeding
- Provides a framework for repair and healing
When a blood vessel is injured, two converging pathways lead to clot formation:
1. Intrinsic (the contact activation): pathway is activated when vessel wall damage causes negatively charged subendothelial substances to come into contact with Hageman factor (XII) found in plasma
2. Extrinsic (tissue factor): pathway is activated by tissue factor (TF), a substance released by damaged endothelial cells of the blood vessels
Both pathways converge at factor X and thrombin. Thrombin activates fibrinogen to form fibrin.
Kinin System
Interacts closely with clotting system and functions to activate and assist inflammatory cells. It is activated by tissue factor FXII. Forms other factors that end in the primary product Bradykinin. When inflammatory response is no longer needed, Kininase enzymes in plasma/tissues degrade kinins.
Bradykinin
Causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis.
Cellular Receptors
Mast cells, macrophages, and dendritic cells have evolved a set of receptors referred to as pattern recognition receptors (PRRs) - they are generally expressed on cells in tissues near the body’s surfaces where they monitor the environment for products of cellular damage and infectious microorganisms. PRRs recognize two types of molecule patterns:
1. Pathogen Associated Molecular Patterns (PAMPs): molecules expressed by infectious agents either found on their surface or released as soluble molecules
2. Damage Associated Molecular Patterns (DAMPs): products of cellular damage
Toll-like Receptors (TLRs)
A type of PRR which recognizes a large variety of PAMPs located on the surface of microorganisms
Degranulation
Mast cells release biochemical mediators from their granules into the surrounding tissues within seconds of a stimulus. Substances within granules include histamine, chemotactic factors, and cytokines.
Synthesis
Activated mast cells initiate synthesis of other mediators of inflammation - these mediators include: leukotrienes, prostaglandins, platelet-activating factor, and growth factor
Mast Cells
cellular bags of granules located in loose connective tissues close to blood vessels (i.e., skin, digestive lining, respiratory tract). they are activated through physical injury, chemical agents, immunologic processes, and TLRs. Mediators are released from mast cells in two ways:
1) Degranulation (histamine, chemotactic factors, cytokines)
2) Synthesis
Histamine
Causes temporary and rapid constriction of the large blood vessels and dilation of the postcapillary venules
H1 Receptor (proinflammatory): is present in smooth muscle cells of the bronchi
H2 Receptor (anti-inflammatory): is present on parietal cells of the stomach mucosa - induces the secretion of gastric acid
Leukotrienes
Are the product of arachidonic acid from mast cell membranes and have similar effects to histamine, they are more important in the later stages of inflammation
Prostaglandins
Have a similar effect to leukotrienes; they also induce pain
Platelet-activating factor
Effect is similar to leukotrienes; they also activate platelets
COX1 & COX2
COX1: produces prostaglandins that activate platelets and protect the stomach lining
COX2: activates prostaglandins associated with inflammation
NSAIDs inhibit COX1 and/or COX2 they suppress inflammation and improve symptoms but have associate side effects. NSAIDs can cause GI tract bleeding, hypertension, renal dysfunction, and cardiovascular disease.
Macrophages
Are derived from circulating monocytes. As with other blood cell types, monocytes are produced in bone marrow and enter into the circulation. They migrate to tissues throughout the body where they transform to macrophages. These tissue macrophages have different names depending on where they are located: Kupffer Cells (Liver), Alveolar macrophages (Lungs), and Microglia (brain)
Interleukins
Are a cytokine produced primarily by macrophages and lymphocytes in response to a microorganism or stimulation by other products of inflammation and help to regulate inflammation by:
1. Regulation of cell adhesion molecules (CAMs) which are proteins that facilitate leukocyte binding with other cells or with the extracellular matrix
2. Attraction of leukocytes to a site of inflammation (chemotaxis)
3. Induction, proliferation, and maturation of leukocytes in bone marrow
4. General enhancement or suppression of inflammation and the adaptive immune response
Interferons
Are cytokines that protect against viral infections and modulate inflammatory response. They are produced and released by virally infected host cells in response to viral double-stranded ribonucleic acid (RNA). They do not directly kill viruses but prevent them from infecting additional healthy cells. Types:
- IFN-a and IFN-b induce the production of antiviral proteins
- IFN-y increases microbiocidal activity of macrophages
Chemokines
Are cytokines that primarily attract leukocytes to the site of inflammation and are produced by macrophages, fibroblasts, and endothelial cells. More than 40 different kinds exist.
Phagocytes
- Neutrophils: first to arrive, short to live - ingest dead cells, bacteria and cellular debris and eventually become part of purulent exudate
- Eosinophils: primary defense against parasites and help regulate vascular mediators
- Basophils: Associated with allergies and asthma
Dendritic Cells
Specialized type of macrophage located in the peripheral organs and skin and provide a link between innate and acquired immune responses. They migrate to lymphoid tissue and interact with T lymphocytes to cause an acquired immune response. They also guide the development of T-cells (helper cells)
Considerations for pediatric innate immunity
Neonates:
- have transiently depressed inflammatory and immune function
- have neutrophils that are not capable of efficient chemotaxis
- have a deficient complement system
- are deficient in collectins and collectin-like proteins
