01 Inflammation Flashcards
Protective response to rid the body of the cause of cell injury and the resultant necrotic cells that cell injury produces
Inflammation
Restores homeostatic balance, fights disease, and drives wound-healing responses
“Little” Inflammation
Results in pathologic conditions such as asthma, rheumatoid arthritis, inflammatory bowel diseases, gout, atherosclerosis, and possibly cancer.
“Lot of” Inflammation
Cardinal Signs of Acute Inflammation
- Rubor (red discoloration)
- Calor (heat)
- Dolor (pain)
- Tumor (mass effect)
- Loss of function
Physiological Effects of Acute Inflammation
- Vasodilation
- Increased vascular permeability
- Recruitment of neutrophils
EDEMA
What causes these physiological effects?
- Vasodilation
- Increased vascular permeability
- Recruitment of neutrophils
- Edema
Acute Inflammation
What causes acute inflammation
microbial infection, physical agent, irritants/corrosive chemicals, tissue necrosis
Action via PMNs
What is the cause of chronic inflammation?
persistence of irritant, endogenous antigen or “factor”
Persistence of irritant endogenous antigen or “factor” can lead to what?
Chronic Inflammation
Leads to upregulation of damage/apoptosis and auto-amplification of the inflammatory response
Fibrosis
What are the harmful effects of inflammation?
- Release of lysosomal enzymes (collagenases and proteases) may digest normal tissue
- Inflammatory swelling may result in death from obstructing airways or swelling within the cranial cavity
Mediator Theory
signs and symptoms of inflammation are caused by the release of chemicals (mediators) from inflammatory and structural cells
Histamine
Inflammatory Mediator
Biogenic amine
Source: Mast cells, basophils
Phys:
- vasodilation
- increased vascular permeability
- pain
Mech: GPCR activation
Tx: Antihistamines (H1 antagonists)
What inflammatory mediator is released specifically from mast cells and basophils?
Histamine
What inflammatory mediators causes:
- vasodilation
- increased vascular/microvessel permeability
- pain
Histamine and Bradykinin
Bradykinin
Inflammatory mediator
Peptide
Source: Endothelial cells
- activated by tissue injury, allergic reactions, viral infections
Phys:
- vasodilation
- increased microvessel permeability
- pain
Mech: GPCR activation
Tx: BK receptor antagonist
What causes increased microvessel permeability?
Bradykinin
Complement System (Inflammatory Mediator)
Plasma proteins
Source: Synthesized by liver, circulates in blood
Phys:
- Chemotaxis
- Promote release of mediators from neutrophils
- Increase vascular permeability
- Excessive activation leads to tissue injury
Mech:
- Aggregate to cell surface and cause osmotic lysis
- GPCR activation
Tx:
- Eculizumab inhibits C5 cleavage
- APT070 is a truncated CR1 which regulates overproduction of completment
What inflammatory mediators increase vascular permeability?
Histamine and Complement System
What inflammatory mediator causes chemotaxis?
Complement System
What inflammatory mediator promotes the release of mediators from neutrophils?
Complement System
What inflammatory mediator with excessive activation can contribute to tissue injury?
Complement System
C-Reactive Protein
Inflammatory Mediator
Plasma Protein
Source: Synthesized in liver and adipocytes in response to cytokines
Phys:
- Acute phase reactant
- Activates complement cascade
- Mediates phagocytosis
- Marker of inflammation
Mech: bind to phospholipids in bacteria and damaged cells (Ca2+ dependent)
Tx: Elevated CRP associated with inc risk of DM, HTN, CV disease. Statins may be effective.
What inflammatory mediator is produced in the liver in response to cytokines as well as in adipocytes?
C-Reactive Protein
What inflammatory mediators are an acute phase reactant?
C-Reactive Protein and cytokines TNF−α and IL−1
What inflammatory mediator activates complement cascade?
C-Reactive Protein
What inflammatory mediator mediates phagocytosis?
C-Reactive Protein
What inflammatory mediator is a marker of inflammation?
C-Reactive Protein
What inflammatory mediator binds to phospholipids in bacteria and damaged cells?
C-Reactive Protein
An elevated level of what inflammatory mediator is associated with an inc risk of DM, HTN, and CV disease?
C-Reactive Protein
Cytokines
Inflammatory Mediator
Proinflammatory cytokines: Interleukin-1 (IL-α and IL-β) and Tumor Necrosis Factor-α (TNF−α)
Source: nearly all inflammatory cells
Phys:
- TNF−α: acute phase reaction, fever, sepsis
- IL−1: acute phase reaction, fibroblast and lymphocyte proliferation, fever
Mech: Induce gene expression of many proteins via NFkB and AP-1
- increase cyclooxygenase (fever) and lipoxygenase
- increase adhesion molecule expression
- induce collagenase (fibrosis)
Tx:
- Entanercept
- Infliximab
What are the proinflammatory cytokines?
Interleukin-1 (IL-α and IL-β) and Tumor Necrosis Factor-α (TNF−α)
What inflammatory mediator causes acute phase reaction, fever, and sepsis?
TNF−α
What inflammatory mediator causes acute phase reaction, fibroblast and lymphocyte proliferation, and fever?
Interleukin-1
What inflammatory mediator causes the activation of NFkB and AP-1?
Proinflammatory cytokines: Interleukin-1 (IL-α and IL-β) and Tumor Necrosis Factor-α (TNF−α)
What is the result of activating NFkB and AP-1 by Interleukin-1 TNF−α?
Increase cyclooxygenase (fever) and lipoxygenase
Increase adhesion molecule expression
Induce collagenase
What is treated with Etanercept or Infliximab?
Pro-inflammatory cytokines Interleukin-1 (IL-α and IL-β) and Tumor Necrosis Factor-α (TNF−α)
What causes an increase in cyclooxygenases (fever) and lipoxygenases?
Activation of NFkB and AP-1 by pro-inflammatory cytokines Interleukin-1 (IL-α and IL-β) and Tumor Necrosis Factor-α (TNF−α)
What inflammatory mediators induce collagenase (fibrosis)?
Activation of NFkB and AP-1 by pro-inflammatory cytokines Interleukin-1 (IL-α and IL-β) and Tumor Necrosis Factor-α (TNF−α)
Adenosine
Inflammatory Mediator
Purine nucleoside formed from ATP breakdown
Source: all cells
Phys:
- Anti-inflammatory: Increased extracellulary during injury
- Inhibits cytokine action
Mech: GPCR activation
Tx: Adenosine A2 agonists
What inflammatory mediator is increases extracellularly during injury?
Adenosine (anti-inflammatory)
What inflammatory mediator inhibits cytokine action?
Adenosine (anti-inflammatory) and glucocorticoids
Cell Adhesion Molecules (CAMs)
Inflammatory Mediator
Family of Proteins
Source: endothelial cells, platelets, leukocytes
Phys:
- Leukocyte adhesion to endothelium is a pivotal event in host defense and tissue repair
- Endothelial adhesion molecules contribute to recruitment of activated platelets
Mech: “contact molecules” calcium dependent
Tx: Abciximab or Natalizumab
What inflammatory mediator causes leukocyte adhesion to endothelium?
Cell Adhesion Molecules
What inflammatory mediator contributes to recruitment of activated platelets?
Endothelial (Cell) adhesion molecules
Oxygen-Derived Free Radicals
Superoxide, hydroxy radicals
Source: all cells
Phys: Intracellular killing of bacterial by neutrophils
Mech:
- protein oxidation
- lipid peroxidation
- DNA mutations
Tx: anti-oxidants Vit C and E
What inflammatory mediator causes intracellular killing of bacteria by neutrophils?
Oxygen-derived free radicals
What inflammatory mediator works via protein oxidation, lipid peroxidation, and DNA mutations?
Oxygen-Derived Free radicals
What are the lipid inflammatory mediators?
Prostaglandins, Leukotrienes, and Glucocorticoids
Prostaglandin
Lipid Inflammatory Mediator
Eicosanoids, Steroids
Source: virtually all cells
Phys:
- Vasodilation/vasoconstriction
- Pain
- Fever
- Platelet aggregation (via thromboxane)
Mech: GPCR activation
Tx: NSAIDs
What inflammatory mediator causes:
- Vasodilation/vasoconstriction
- Pain
- Fever
- Platelet aggregation (via thromboxane)
Prostaglandin (Lipid mediator)
What inflammatory mediator is treatment for chronic inflammatory diseases?
Glucocorticoids
What inflammatory mediator is treated with NSAIDs?
Prostaglandins (Lipid mediator)
Leukotriene
Lipid inflammatory mediator
Source: macrophages, neutrophils
Phys:
- Inc vascular permeability
- Bronchoconstriction
Mech: GPCR activation
Tx:
- Zileuton (5-lipoxygenase inhibitor)
- Zafirlukast (cys-leukotriene receptor antagonist)
What inflammatory mediator causes:
- Inc vasc permeability
- Bronchoconstriction
Leukotrienes (lipid mediator)
5-lipoxygenase inhibitor
Zileuton (Tx of leukotriene)
Cys-leukotriene receptor antagonist
Zafirlukast (Tx of leukotriene)
Glucocorticoids
Lipid inflammatory mediator
Source: Adrenal cortex
Phys:
- Inhibition of cytokines
- inhibition of phospholipase A2
- inhibition of cyclooxygenase-2
- inhibition of cell adhesion molecules
Mech: nuclear receptor activation
Tx: Steroids (controlling chronic inflammatory diseases)
What inflammatory mediator inhibits cyclooxygenase-2?
Glucocorticoids (lipid mediator)
What inflammatory mediator inhibits cell adhesion molecules?
Glucocorticoids (lipid mediator)
What inflammatory mediator is used to treat chronic inflammatory diseases?
Glucocorticoids
What is the mechanism of steroids (glucocorticoids)?
Bind to cytoplasmic receptors
activated receptor-steroid complex localizes to nucleus/binds DNA (glucocorticoid response elements) resulting transcription of certain target genes (induction or repression)
Inhibits cytokines, protaglandins, leukotrienes, cell adhesion molecules
What is the mechanism of action of non-steroidal anti-inflammatory drugs?
Inhibition of cyclooxygenase
Leukotriene Antagonists
Zafirlukast
Zileuton
Zafirlukast
competitive antagonist of leukotriene receptors
Zileuton
Inhibits the synthesis of leukotrienes
Inflammatory Cytokine Inhibitors
Etanercept
Infliximab
What is the Acute Phase Reaction?
In response to injury, local inflammatory cells secrete cytokines that cause the liver to increase or decrease production of various proteins
What mediator contributes to signs and symptoms of inflammations (pain, fever, vasoactive effects)?
Prostaglandins
What mediator directly increases blood flow and indirectly enhances edema formation and leukocyte infiltration?
Prostaglandins
What mediator releases slow reacting substance of anaphylaxis (SRS-A) from mast cells?
Leukotrienes
What mediator is increased in allergies/asthma?
Leukotrienes
What mediator causes vasodilation?
Prostaglandins
What mediator causes increased vascular permeability?
Vasoactive amines
Complement Proteins
Bradykinin
Leukotriene
What mediator causes chemotaxis?
Complement Protein
Leukotrienes
What mediator causes fever?
Cytokines IL-1 and TNF-alpha
Prostaglandins
What mediator causes pain?
Prostaglandins and Bradykinin
What mediator causes tissues damage?
Neutrophil and macrophage lysosomal enzymes
Oxygen metabolites