Inflammation Flashcards
Define inflammation.
Response of vascularized tissue to infection and damaged tissues that brings cell and molecules of host defense from the circulation to sited where they are needed in order to eliminate offending agents
What are the signs of inflammation?
• Heat (calor)
• Redness (rubor)
• Edema (tumor)
• Pain (dolor)
• Loss of function (functio laesa)
What are the goals of inflammation?
Destroys invading microorganisms
Contains and isolate injury
Inactivate toxins
Prepare tissues for healing and repair
What are the harmful effects of inflammation?
May cause life threatening hypersensitivity reaction.
Underlies some common chronic diseases (rheumatoid arthritis, atherosclerosis, lung fibrosis)
Repair by fibrosis may lead to scars or fibrous tissues or permanent organ damage
Compare the two types of inflammation?
Acute: Rapid onset, short duration, exudation of fluid and plasma proteins, emigration of predominantly neutrophils
Chronic: longer duration, associated with lymphocytes, plasma cells and monocytes/macrophages, proliferation of blood vessels, fibrosis and tissue injury
What are the steps of the inflammatory response?
- Recognition of the injurious agent
- Recruitment of leukocytes
- Removal of the agent
- Regulation (control) of the response
- Resolution (repair)
What is the stimuli for acute inflammation?
Infections: bacteria, viruses, fungi, parasites
Physical and chemical agents: heat, trauma, cold, ionizing, radiation, acids, bacterial toxins
Tissue necrosis: from ischemia & physical and chemical injury
Foreign bodies: sutures, dirt, contact lenses
Immune reactions: hypersensitivity, autoimmune reactions
What mechanisms do we have for recognition of harmful agents?
PRR: on phagocytes, dendritic, epithelial cells sense infectious pathogens and substances from dead cells (activated by PAMPs and DAMPs)
Circulating proteins recognize microbes that have entered blood (mannose-binding proteins collections)
Sensors of cell damage (Uric acid- DNA damage, decreased K- plasma mem damage, DNA in cytoplasm)
What are the 2 major components of acute inflammation?
Vascular changes: vasodilation (increase blood flow), increase in vascular permeability (structural changes allow plasma proteins and leukocytes to leave circulation to produce inflammatory exudates)
Cellular events: cellular recruitment and activation (emigration of leukocytes from bv to focus of injury, activation to eliminate offending agent)
Define vasodilation during acute inflammation.
– earliest manifestation
– involves the arterioles then results in opening of new capillary beds
– increased greater blood flow to the area of inflammation, resulting in redness (rubor) and heat (calor)
– induced by mediators such as histamine and nitric oxide
Define vascular permeability in acute inflammation.
Endothelial cells become leaky from direct endothelial injury or chemical mediators
Leads to escape of proteins rich fluid into the extra vascular tissue (exudation to edema)
Define vascular stasis in acute inflammation.
Loss of fluid results in concentration of RBC in small vessels and increased viscosity of blood and slowing of the blood in the blood stream
Changes cause by numerous dilated small vessels packed with erythrocytes
Define exudation in acute.
Escape of fluid, proteins and blood cells from the vascular system into the interstitial tissue or body cavities
Describe serous (transudate) exudate.
Relatively mild inflammation
Low protein content, relatively clear fluid
Blisters, sunburn, shingles, cold sores
Describe fibrinous exudate.
Severe injuries or inflammation
Difficult to resolve
Ex: in anterior chamber
Describe purulent exudate (pus).
Thick, yellowish-white
Contains protein rich fluid, necrotic debris, leukocytes (mostly neutrophils)
Often due to bacterial infection
May form inside abscess
Ex: Chlamydial infection, Haemophilis influenza infection, abscess
Compare hard and soft exudates of the posterior pole.
Hard- lipid residues of serous leakage from damages capillaries, diabetic ret
Soft- cotton wool spots, accumulation of axoplasmic material, ischemia
Describe extravasation.
Delivery of leukocytes to site of injury
Leukocytes ingest offending agents, kill bacteria. Get rid of foreigners and necrotic tissue
What are the three steps of extravasation.
1) Margination, rolling, & adhesion of leukocytes in the lumen
2) Transmigration across the endothelium (also called diapedesis)
3) Migration through interstitial tissue toward a
chemotactic stimulus
Describe margination in extravasation.
Accumulation of leukocytes at the periphery of vessels
Smaller RBC move faster than larger WBC
Better opportunity to interact with lining endothelial cells
Describe rolling in extravasation. What mediates it?
Binding, detaching, and tumbling of leukocytes along the endothelial surface
Mediated by selectin (adhesion molecule)
Describe adhesion in extravasation. What mediates it?
Firm attachment of leukocytes to endothelial cells
Mediated by integrins
TNF and IL-1 activate Endo cells to increase expression of ligands for integrins
Shape change to leukocytes mediate attachment to substrate
Describe transmigration. What mediates it?
Leukocytes squeeze between cells at intercellular junctions (diapedesis)
Mediated by chemokines produced in extravascular tissue
Mediated by PECAM-1
What are adhesion molecules? Examples?
Involved in leukocyte recruitment
Ex: selections, integrins, PECAM-1
Describe Selectins.
Weak adhesions involved in rolling
Extracellular domain that binds to sugar (sialyl Lewis-X moiety) allows for attachment and rolling
P-selectin (platelets, endothelial cells)
E-selectin (endothelial cells)
L-selectin (leukocytes)
Histamine, thrombin, or other inflammatory cytokines can result in increased movement of P-selectins to the cell surface
IL-1 and TNF stimulate expression of selectins
Describe integrins.
Involved in adhesion
On leukocyte surface adhere after chemokine activation, shape change and cluster for high affinity form
TNF and IL-1 activate Endo cells to increase expression of ligands (ICAM-1 and VCAM-1) for integrins
ICAM-1 ligand binds to LFA-1 integrin and Mac-1 integrin
VCAM-1 ligand bind to VLA-4 antigen
Describe the mechanism for lifitegrast which is in Xiidra
(dry eye).
Inhibits T cell adhesion to ICAM-1 cells and inhibits secretion of pro-inflammatory cytokines (interferon y, TNF-a, IL)
Xiidra is a lymphocyte function-associated antigen 1 (LFA-1)
Integrin to ligand adheres cells to curface, this binding can be inhibited to prevent inflammation
What are the potential roles of the LFA-1/ICAM-1 interaction in the eye?
Homing of dendritic cells to the lymph nodes
T-cell activation and differentiation
T-cell migration to the ocular
Trigger inflammation
Describe PECAM-1.
Transmigration
Platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31)
Expressed on leukocytes and endothelial cells
Mediates the binding events needed for leukocytes to traverse the endothelium
Describe chemotaxis involved in migration.
Leukocyte emigrate in tissue toward injury by chemotaxis
Exo and endogenous substances can act as chemoattractants
Exo- bacterial products (possess N-formyl-methionine terminal amino acid or lipids)
Endo- C5a, leukotriene B4, IL-8
Describe the steps involved in chemotaxis.
Binding of chemoattractants
G-protein medicated signal transduction (some cause increased cytosolic calcium which trigger contraction for movement)
Leukocytes move by extending pseudopods that anchor to ECM and pull
How long does it take for neutrophils to infiltrate during acute inflammation? Are there any variations?
Type of emigrating leukocyte varies with the age of the
inflammatory response and with the type of stimulus.
In most forms of acute inflammation, neutrophils
predominate in the inflammatory infiltrate during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hours
What is the stimuli for and function of leukocyte activation?
Stimuli: microbes, products of necrotic cells &
mediators
Functions:
– Intracellular destruction of phagocytosed microbes
and dead cells
– Liberation of substances that destroy extracellular
microbes and dead tissues
– Production of mediators
Describe the function of lymphatic vessels in inflammation.
Increased lymph flow in inflammation
Drains edema, leukocytes and cell debris
Transports microbes
Define lymphangitis.
Inflamed lymphatics
Define lymphadenitis.
Inflamed lymph nodes
Enlarged due to hyperplasia of lymphoid follicles, increased number of lymphocytes and phagocytic cells lining the sinuses of lymph nodes
Describe the termination of the inflammatory response.
Neutralization, decay, or enzymatic degradation of chemical mediators
Normalization of vascular permeability
Cessation of leukocyte emigration
Death (by apoptosis) of extravasated neutrophils Leukocytes begin to produce mediators that inhibit inflammation
The necrotic debris, edema fluid, and inflammatory cells are cleared by phagocytes and lymphatic drainage
What are the outcomes of inflammation?
Complete resolution: regeneration of native cells, restoration of site of acute inflammation to normal
Progression to chronic inflammation
Healing by fibrosis and scarring
