Inflammation Flashcards
Beneficial goals of inflammation
Destroying/containing harmful agent
Preparation for healing/repair
Four cardinal signs of inflammation
Calor (heat) Rubor (redness) Tumor (swelling) Dolo (pain) *Functio lasea (loss of function)*
Acute Inflammation Features: Onset, Cellular infiltrate, tissue injury, fibrosis, local and systemic signs
Onset: Fast, minute or hours
Cells: Mainly neutrophils
Tissue injury: Usually mild and self-limited
Local and systemic signs: Prominent
Chronic Inflammation Features: Onset, Cellular infiltrate, tissue injury, fibrosis, local and systemic signs
Onset: Slow, days
Cells: Monocytes/macrophages and lymphocytes
Tissue: Often severe and progressive
Local and systemic signs: Less prominent; may be subtle
Acute Inflammation Stimuli
Infections and microbial toxins (bacteria, viruses, fungi, parasites)
Physical trauma
Physical and chemical agents (burns, frostbite, irradiation, environmental chemicals)
Tissue necrosis (any kind(
Foreign bodies (splinters, dirt, sutures, crystal deposits)
Immune (hypersensitivity)
Initiation - Stimulus recognition cells
Epithelial cells
Dendritic cells
Phagocytes
Initiation - Receptors
Toll-like receptors
Inflammasome
Where are TLRs located?
Located in plasma membrane
What do TLRs recognize?
Bacteria, viruses, and other pathogens
What do TLRs do when activated?
Release of cytokines (TNF)
What/where is the inflammasome?
Cytoplasmic complex
What does the inflammasome recognize?
Dead cells (uric acid, ATP, crystals, some microbial products)
What does the inflammasome do upon activation?
Activation of caspase-1, activating IL-1, triggering leukocyte recruitment
Vascular changes - Vessel caliber and flow
Vasodilatation induced by chemical mediators such as histamine and NO
Leads to stasis and margination of leukocytes
Vascular changes - Permeability changes
Endothelial cell contraction (histamine, bradykinin, etc.) and endothelial cell injury - directly injured by burns, microbes, neutrophils resulting in increased vascular permeability and subsequent edema
Vascular changes - Lymphatic vessel response
Increased flow allows drainage of edema fluid and cellular debris
Occasionally lymphangitis/lymphadenitis occurs (secondary infection/inflammation of lymphatic vessels/lymph nodes)
Role of histamine mediation
Mast cell release
Vasodilation and increased vascular permeability
Role of nitric oxide mediation
Endothelial cell response to injury
Vasodilation
Bradykinin
Kinin system activation from endothelial injury
Vasodilation, increased permeability, and pain
Transudate
Hypocellular & low protein content
Non-inflammatory extravascular fluid, low specific gravity: <1.012
Exudate
Cellular and protein rich
Inflammatory extravascular fluid; high specific gravity: >1.020
Pus
Purulent exudate rich in leukocytes
Margination
Leukocyte accumulation at periphery of vessels
Rolling
Weak & transient adhesions to endothelium
Uses selectins
Adhesion
Firm adhesion to endothelium
Uses integrins
Transmigration
Movement through endothelium to interstitium
Diapedis (movement of leukocytes through vessel wall)
Cells squeeze between endothelial cells
Chemotaxis
Movement towards injury site in the interstitium
Where is selectin found?
Endothelial (E-), Platelet (P-), Leukocyte (L-)
What on the leukocyte binds to selectin?
Sialyl-Lewis glycoprotein
What causes presentation of selectins?
Mediators (histamine, thrombin)
What kind of attachment does selectin do?
Loose attachment
Where is integrin found?
Leukocytes
How are integrins activated?
Chemokine expression on endothelial cells activate integrins
What kind of attachment does integrin do?
Stable attachment of leukocytes to endothelium
What drives transmigration?
CD31 (PECAM1) on leukocytes & endothelial cells
What are some chemotactic factors?
Chemokines, complement, leukotrienes
When are leukocytes activated?
After recruitment to site of injury
What do leukocytes do? (4 things)
Phagocytosis
Intracellular destruction
Release of substances that destroy tissue & microbes
Increase mediator production
How are microbes recognized by leukocytes?
1) Specific surface receptors
2) Opsonins (IgG, Complement, Lectins)
Steps of phagocytosis
- Recognition and attachment
2,. Engulfment by phagocyte membrane around microbe - Phagosome fusion with lysosome
- Oxidative burst
- Secretion of enzymes into extracellular space to degrade microbes & dead tissue
Principal mediators of vasodilation
*Histamine
*Nitric oxide
Prostaglandins
Principal mediators increased vascular permeability
*Histamine
*Bradykinin
C3a, C5a
Leukotrienes C4, D4, E4
Platelet activating factor
Substance P
Principal mediators chemotaxis, leukocyte recruitment and activation
*IL-1, TNF
*Bacterial products
Chemokines
C3a, C5a
Leukotriene B4
Fever
IL-1, TNF, PGE2
Pain
*Bradykinin
Prostaglandins
Tissue damage
*ROS
*Nitric oxide
Lysosomal enzymes of leukocytes
What are the most common causes of leukocyte defects? (Specifically production, adhesion/taxis, phagocytosis/microbicidal)
Overall it is acquired causes not genetic
Production: Bone marrow suppression
Adhesion: Sepsis, diabetes, dialysis, malignancy
Phagocytosis & microbicidal activity: Sepsis, diabetes, anemia, malnutrition
Possible outcomes of acute inflammation
Resolution
Chronic inflammation
Scarring or fibrosis
Serous inflammation
Mildest form of acute inflammation
Outpouring of thin fluid (protein-poor) from plasma or serosal cavity linings
Fibrinous inflammation
Occurs secondary to more severe injury
Larger vascular leaks, passage of fibrinogen, conversion to fibrin
Where does fibrinous inflammation affect?
Linings: Meninges, pericardium, pleura, peritoneum
Suppurative (purulent) inflammation
When large numbers of neutrophils are present, with necrotic cells, edema fluid and bacteria to form pus
What kind of bacteria are more likely to produce suppurative inflammation?
Pyogenic bacteria
Abscess
Central area of necrotic tissue surrounded by preserved neutrophils, vessels, fibroblasts
Ulcer
Sloughing of surface of an organ or tissue covering necrotic inflammatory tissue
Duration of chronic inflammation
Weeks to months to years
Active inflammation, tissue injury & healing occur at same time
Causes of chronic inflammation
Persistent infections
Prolonged toxic exposure
Immune-mediated inflammatory diseases (autoimmunity)
What happens to macrophages during chronic inflammation?
They persist
Constant stimulation by dead cells, microbes, activated T cell cytokines (IFN-gamma)
Resuls in continued tissue injury
What other cells are involved in chronic inflammation?
Lymphocytes
Plasma cells
Eosinophils
Mast cells
What do lymphocytes do in chronic inflammation?
T&B migrate to site
Respond to chemokines
Interact with macrophages
What do plasma cells do in chronic inflammation?
Immunoglobulin production against persistent antigens
What do eosinophils do in chronic inflammation?
Release major basic protein which is toxic to parasites & epithelium
What do mast cells do in chronic inflammation?
Activated by IgE for environmental antigens
Release histamine and arachidonic acid metabolites
Central in allergic & anaphylactic reactions
Granulomatous inflammation (Morphology, Stimulus, Causes)
Morphology: Distinctive pattern of chronic inflammation with prominent macrophages with an epithelioid appearance. Formation of multinucleated giant cells due to IFN-gamma with a collar of lymphocytes and plasma cells
Stimulus: Develop in response to specific infections, inert foreign bodies, autoimmunity
Causes: Can be caused by infectious and non-infectious causes
What is the name for the systemic effects of inflammation?
Acute phase reaction or systemic inflammatory response syndrome (SIRS)
What are the major clinical changes due to SIRS?
Fever
Elevated plasma levels of acute-phase proteins
Leukocytosis
What is fever in response to?
Pyrogens (general term)
Exogenous: LPS from bacteria
Endogenous: IL-1, TNF release from leukocytes
What is the process of temperature change?
Prostaglandine (PGE2) release
Stimulates hypothalamus to increase temperature set point
What stimulates elevation of acute-phase proteins?
IL-6
What acute-phase proteins are formed?
C-reactive protein, Fibrinogen, Serum amyloid A protein
What actions do acute-phase proteins do?
Bind to microbe wall aiding in elimination
Fibrinogen binds to erythrocytes causing stacks (rouleaux) that sediment more rapidly than normal
What stimulates leukocytosis?
TNF & IL-1
Leukocytosis
WBC count increases typically 15,000-20,000
Accelerated release of cells from bone marrow
What is the leukemoid reaction?
Extreme leukocytosis (>20,000)
Specific types of leukocytosis and underlying causes
Neutrophilia - Bacterial infection
Lymphocytosis - Viral infections
Eosinophilia - Allergies, asthma, parasitic
Leukopenia - Typhoid, rickettsiae, some protozoans
