Exam 2 Flashcards
What vascular and cell processes commonly occur in inflammation?
Increased blood flow
Increased vascular permeability
Leukocytic exudation through vessels
(Margination/rolling, Adhesion and migration, Chemotaxis and activation)
List 5 signs that often accompany inflammation and describe the pathophysiologic basis of these signs.
a. Rubor (redness): increased blood to the area
b. Tumor (swelling)- increased permeability
c. Calor (heat): body temp goes up due to cytokine mediators and increased BF
d. Dolor (pain): stimulation of free nerve endings
e. Functiolaesa (loss of function)
The process of reaction of living vascularized tissue to injury
Inflammation
List 5 chemicals mediators that can mediate an increase in vascular permeability at a site of inflammation?
histamine C3a, C5a Bradykinin, Leukotrienes (C4/D4/E4) Platelet Activating factor (PAF)
List 3 chemical mediators of cells
Vasoactive amines: histamine, serotonin
Prostaglandins and leukotrienes: PGE2, LTB4
Cytokines/chemokines: TNF alpha, IL-1, IL-8, MIP-1
Nitric Oxide
How does C5a contribute inflammatory reactions?
Increase vascular permeability
Chemotactic for neutrophils, eosinophils, and macrophages
Cause mast cell degranulation, smooth muscle contraction, secretion of neutrophil granules
Stimulates oxygen radical production in neutrophils and macrophages, and arachadonic acid metabolism
How do Coagulation/Fibrinolytic products contribute inflammatory reactions?
chemotactic for PMN’s and macrophages through fibrinopeptide formation
What cells release vasoactive amines and arachidonic metabolites and are important in regulating inflammation?
Vasoactive amines: Mast cells, basophils, platelets
AA metabolites:
resident cells, leukocytes, and mast cells (PGE2) and
Neutrophils, Macrophages, eosinophils (leukotrienes)
???
What pathogenic mechanisms are responsible for edema in inflammatory reactions?
Increased vascular permeability and vasodilation allows plasma proteins to leak into the ECM, altering oncotic pressure, allowing fluid to follow
Why are neutrophils often the first inflammatory cells to reach a site of injury during an acute inflammatory reaction?
Highly motile and high phagocytic rate
Respond to a wide variety of chemotactic stimuli, which enables them to respond quickly and efficiently
What properties of macrophages allow for them to function effectively in a chronic inflammatory process?
Much longer life, can phagocytize more than once
effective in destruction and long-term digestion of phagocytosed particulates
C3a’s role in inflammation
increase vascular permeability
What are the 2 vasoactive amines
histamine and serotonin
What is the role of vasoactive amines in inflammation?
vasodilation
Increased venular permeability
Bronchial and other smooth muscle contraction
Source of prostaglandins
resident cells, leukocytes, mast cells
Inflammatory effects of Prostaglandins
- Increase vascular permeability (PGE2)
- Increase blood flow
- Inhibit fibroblast and lympho proliferation
- Increase body temp
- Stimulate pain receptors
Source of leukotrienes
neutrophils, macrophages, and eosinophils
Inflammatory effects of LTB4
chemotactic for neutrophils and eosinophils and chemokinesis for monocytes/macrophages
MOST potent neutrophil chemotactic substance
leukotrienes (LTB4)
Inflammatory effects of LTD4/C4/E4
smooth muscle contraction, increase vascular permeability
What cell surface molecules on leukocytes and endothelial cells play a role in regulating leukocyte rolling and margination?
a. E selectins: endothelial cells (upregulated by TNF alpha and IL 1)
b. P selectins: endothelial cells
c. Sialylated oligosaccharides: leukocytes
List 2 stimuli that can upregulate E selectins and the process of migration and margination of leukocytes
TNF alpha and IL 1
How do neutrophils and macrophages mediate tissue injury during an inflammatory reaction?
Via release of lysosomal enzymes and oxygen radicals
Macrophages, also, release their cytokines which can induce damage
An inflammatory cell that is long-lived, can divide locally in tissue and regulates immune and repair responses:
a) Neutrophil
b) Eosinophil
c) Macrophage
d) Platelet
e) B and C
C
Histamine increases vascular permeability at the level of capillaries and venules through the mechanism of:
a) Endothelial cell contraction
b) Endothelial cell damage
c) Increased transcytosis
d) Induce endothelial proliferation
A
Which cell surface molecules on leukocytes and endothelial cells mediate leukocyte rolling?
E and P selectins on endothelial cells (upregulated by TNF alpha and IL 1)binding to sialylated oligosaccharides on leukocytes
Which cell surface molecules on leukocytes and endothelial cells mediate leukocyte adhesion?
ICAM-1 and VCAM-1 on endothelial cells
Integrins (LFA-1, Mac-1, VLA-4) on leukocytes, which are stimulated by TNF alpha, IL-8 and IL-1
Which cell surface molecules on leukocytes and endothelial cells mediate leukocyte transmigration?
Co expression of PECAM-1 (CD31) on both endothelial cells and leukocytes (homophilic adhesion molecule)
Bovine leukocyte adhesion deficiency is caused by a defect in which gene? How would you detect the abnormality in a carrier animal?
a. CD18 gene
b. Calves have poor neutrophil response to infection by bacteria and common fungi
c. Enteritis and pneumonia
Leukocyte adhesion deficiency in Irish Setter Dogs is associated with a genetic defect in which gene?
CD18 missense mutation
Why do bacterial infections often lead to neutrophil-dominated inflammatory reactions?
Neutrophils are highly motile, high phagocytic capacity, and are the most effective killers of bacteria (strong neutrophil chemotactic factor is the bacterial cell wall)
How do lymphocytes, macrophages, and mast cells amplify or produce inflammatory response?
Release inflammatory mediators (IFN gamma, leukotrienes, interleukins, chemokines, prostaglandins).
Can amplify a reaction by releasing chemicals like oxygen radicals, superoxide anions and lysosomes. This can cause tissue damage too
Neutrophil-Endothelial surface molecules mediating rolling
a) Integrin (CD11/CD18)- selectin
b) Siayl lewis X-selectin
c) Integrin (CD11/CD18)- ICAM-1
d) PECAM-1 (CD31)-PECAM-1 (CD31)
B
Holstein cattle and Irish Setter dogs have mutations in which molecules to develop leukocyte adhesion molecule deficiency
a) Selectin
b) ICAM-1
c) Integrin (CD18)
d) PECAM-1 (CD31)
e) Siayl-Lewis X glycoprotein
C
How are inflammatory reactions commonly classified morphologically?
Duration :acute, sub-acute, chronic
Distribution: focal, multifocal, locally-extensive, diffuse
Type of exudate
Tissue Involved
What are histologic indicators of a chronic inflammatory reaction?
fibrosis
necrotic inflammatory reaction on an epithelial surface down to the basement membrane
erosion
necrotic inflammatory reaction on an epithelial surface that involves LOSS of the basement membrane
ulcer
What pathogenetic events are important in the stimulation of a granulomatous inflammatory reaction?
Inciting stimuli-substances that resist lysosomal degradation and substances that induce T-cell hypersensitivity
Suppurative inflammatory reactions are often induced by? A. Fungi B. Nematode parasites C. Bacteria (non-mycobacterial) D. Mycobacteria E. Toxins
C. Bacteria (non-mycobacterial)
Eosinophilic inflammatory reactions are often induced by a. fungi b. nematode parasites C. Mycobacteria E. Toxins
B
Macrophage dominated inflammatory reactions are often induced by: a. Fungi B. Nematode parasites C. Bacteria (non-mycobacteria) D. Mycobacteria E. Toxins
A and D
Which type of inflammatory cell is often associated with liquefactive necrosis? a. Lymphocyte B. Neutrophil C. Macrophage D. Eosinophil E. Mast cell
B. neut
What role does delayed type hypersensitivity play in the pathogenesis of granulomatous inflammation?
Hypersensitivity is NOT a requirement but CAN accelerate and intensify the inflammation response via lymphokines released from T cells.
True or False
Granulomatous inflammation is almost always a chronic process unless there is a pre-existing T cell hypersensitivity.
TRUE
Inflammatory reaction dominated by macrophages
Granulomatous
Compact and organized collection of mononuclear inflammatory cells dominated by macrophages
granuloma
highly organized fibrovascular tissue that often replaces necrotic cells and areas where poor regeneration has occurred
Granulation tissue
Granuloma with central necrosis +/- calcification
complex granuloma
Inciting stimuli of granulomatous inflammation are?
a) Particulates resisting lysosomal degradation
b) Persisting molecules that stimulate T-cell hypersensitivity
c) Stimuli that are chemotactic for macrophages and neutrophils
d) A, B
e) A, B, C
D
Granulomatous inflammation is almost always:
a) Acute
b) Chronic
B
Inflammatory cells central to granulomatous inflammation
a) Macrophages
b) Epithelial cells
c) Multinucleated giant cells
d) A,B,C
e) A, C
E
process resulting in increase of collagen in tissue; often an important and sometimes necessary component of the repair process
Fibrosis usually results in fibrous connective tissue
Cells that have latent capacity to regenerate; normally quiescent in G0 state; have long life spans and don’t turnover quickly
Stable
epithelial cells in liver, kidney, lung, endocrine glands; smooth muscle cells, fibroblasts, endothelial cells (also skeletal muscle to an extent) are examples of this kind of cell
stable
Cells that continue to multiply throughout life (never leave cell cycle to G0 state) and replenish those lost due to normal turnover
Liable
epidermal/intestinal epithelial cells, lymphoid and hematopoietic cells are examples of these kind of cells
liable
cells w/ no capacity to regenerate additional cells
Permanent or non-dividing cells
neurons and cardiac cells are examples of these kind of cells
permanent
Cell migration along a concentration gradient of chemical mediatory
chemotaxis
Random migration stimulated by a mediator
chemokinesis
What do non-dividing cell do in response to injury
limited capacity to regenerate some cell cytoplasm therefore only repair by scaring
Process by which lost or necrotic cells are replaced by vital cells
repair
replacement of cells by cells of the same type aka good
regeneration
damage cells are replaced by connective tissue
fibrosis aka bad
small chemotactic cytokines produced by macrophages, stroll cells, and epithelial cells
chemokines
Two examples of broad chemokines and their spectrum of biological activities
CXC chemokines- primarily for neutrophils and endothelial cells (e.g. IL8 and factor 4)
CC chemokines- chemotactic for mononuclear cells (lymphs, mono) and eos (MIP1, Rantes, Eotaxin)
4 cytokines that regulate the inflammatory and/or repair process
TNF alpha
IL-1
IFN gamma
Chemokines
Released from macrophages and other inflammatory cells and fibroblasts in response to viral and fungal infections, endotoxins and chemical injury.
Upregulates endothelial adhesion molecules, promotes production of cytokines and mediators and induces acute phase proteins
TNF alpha and IL-1
Has similar actions to TNF alpha and cachexia
IL-1
Produced by T cells and NK cells during Ag driven inflammatory response. Upregulates macrophage function, increases macrophage killing capacity and giant cell fusion
IFN gamma
What general molecular events might explain why transforming growth factor-beta stimulates fibroblast proliferation and inhibits epithelial proliferation and repair?
Both fibroblasts and epithelial cells have TGF beta, but their second messenger systems must differ. Allowing for upregulation in one cell and down in another.
List three cytokines or growth factors that are released from macrophages that modulate fibrosis and angiogenesis
Fibroblast growth factor (FGF)
Vascular endothelial growht factor (VEGF)
Platelet derived growth factor (PDGF)
Once collagen in a scar is formed is it inert to further change and collagen modification?
No, eventually the scar can resolve and the tissue goes back to almost normal. Collagen is degraded and resynthesized over time
What type of injuries and pathologic processes commonly lead to fibrosis?
- Severe/prolonged injury
- Loss of basement membrane
- Large amount of exudate
- Lack of renewable cells (non-dividing cells)
What type of injuries and pathologic processes commonly lead to regeneration?
- Mild/brief injury
- Maintenance of BM/microvascular/tissue framework
- Small amounts of exudate
- Available renewable cells (stem cells)
Which conditions favor tissue repair by fibrosis following injury?
a) Lack of renewable population
b) Prolonged/severe injury
c) Minimal exudate
d) A,B
e) A,B,C
D
Which tissues are highly susceptible to repair by fibrosis or scarring because they lack dividing renewable cell populations?
a) Renal tubular epithelium
b) Myocardial myocytes
c) Cerebral corticol neurons
d) A,B,C
e) B,C
E
Growth factors and cytokines that lead to epithelial proliferation.migration
b-EGF, HGF KGF
basic, Epithelial growth factor
Hepatocyte Growth Factor aka Scatter Factor (HGF)
Keratinocyte growth factor
Give examples of diseases that are dependent on type IV hypersensitivity phenomena?
TB, contact derm, fungal disease, tissue rejection transplants
Which of the following are potent inducers of angiogenesis?
a) VEGF
b) B-FGF
c) HGF
d) A,B
e) A,B,C
ALWAYS ASKS THIS QUESTION
D
Which of the following is a potent inducer of fibrosis?
a) TGF-beta
b) TNF- alpha
c) PDGF
d) A,B
e) A,B,C
E
What is a morphologic diagnosis, and how does it differ from an etiologic diagnosis?
Morphologic- dx purely on morphology
Etiologic- dx that includes the causative agent
What are IL-8 and eotaxin? What are their functions?
IL-8 CXC chemokine, attracts neutrophils to wound
Eotaxin- CCchemokine, attracts eosinophils to wound
LIST two growth factors that are released by macrophages that strongly promote endothelial growth and angiogenesis.
Here is 3
VEGF, beta- FGF, PDGF
List two growth factors / cytokines released by macrophages that strongly promote fibroblast proliferation and collagen synthesis.
There are several:
TGF-beta, PDGF, TNF, collagenase, MMPs
List two mediators released by macrophages that are strongly chemotactic for neutrophils.
IL-8 and LTB4
How do neutrophils contribute to tissue damage in immune complex injuries?
mediate tissue injury via lysosomal enzymes and oxygen radicals
How do complement fragments (C3a and C5a) contribute to immune complex disease?
Type II Hypersensitivity
May lyse cells or the cells are phagocytized and eliminated by cells of the mononuclear phagocyte series
Which of the following inflammatory mediators induces increases vascular permeability, fever and pain? A. LTB4 B. LXA4 C. C5a D. PGE2 E. Histamine
PGE2 (note that in chart it says just vasodilation, but then on his slide it says it causes vascular perm too)
LTB4, C5a, histamine- just perm
LXA4- have no idea what that is
Which of the following inflammatory mediators is strongly chemotactic for neutrophils? A. LTB4 B. LXA4 C. C5a D. PGE2 E. A and C
E. LTB4 and C5a
Which of the following mediators is produced by sensitized lymphocytes and is strongly chemotactic for eosinophils? A. Histamine B. LXA4 C. C5a D. PGE2 E. Eotaxin (CCL11)
Eotaxin
Sensitized- therefore a hypersensitive response
List three growth factors that stimulate epithelial proliferation in repair.
EGF, HGF (aka scatter factor), KGF (FGF-7)
Which of the four types of hypersensitivity diseases according to the classification of Gell and Coombs
are dependent on T-lymphocytes versus immunoglobulin?
Type IV hypersensitivity
Generalized anaphylaxis is dependent upon which inflammatory mediators?
Histamine and serotonin: Increase venular permeability, induce smooth muscle contraction
in pulmonary airways, cause arteriolar dilation
How do neutrophils contribute to tissue damage in immune complex injuries?
Formation of antigen-antibody complex in tissue
Fixation of complement and liberation of chemotactic
fragments
Neutrophils accumulation at site of immune complex deposition and mediation of tissue
injury through release of lysosomal enzymes and toxic oxygen radicals
What form of antigen-antibody complex is necessary for immune complex disease to develop?
Just need excess antigen
How do complement fragments (C3a and C5a) contribute to immune complex disease?
Released during the complement cascade and act as chemotactic factors for neutrophils
How do sensitized T-cells contribute to tissue damage in type IV hypersensitivity disease?
lymphokine mediated effects and CD8 mediated toxicity
3 components of cytotoxic T cell action
- Perforin cell membrane lysis (necrosis)
- Perforin-granzyme induced apoptosis
- FASL-FAS induction of apoptosis
Type I anaphylactic hypersensitivity reactions can be mediated by:
a) IgG
b) IgM
c) IgE
d) A,B
e) A, C
E
Type III hypersensitivity reactions can be mediated by:
a) IgG
b) IgM
c) IgE
d) A,B
e) A,C
D
SAID THIS ONE IS IMPORTANT
Tissue injury type IV hypersensitivity/allergic reactions is mediated via?
a) Immune complex formation
b) T-call induction of granulomatous inflammation
c) Direct- T cell cytotoxicity
d) A, B,C
e) B,C
E
Type III immune complex hypersensitivity reactions occur most commonly in a state of
a) Ag excess
b) Ab excess
c) Ag-Ab equivalence
A !!!!!
Examples of Type I hypersensitivity
anaphylaxis, allergic dermatitis
Mechanism of Type I hyper.
mediator release
Examples of Type II hypersensitivity
autoimmune hemolytic anemia
Examples of Type III hypersensitivity
glomerulonephritis
Mechanism of Type II hyper.
cytotoxic via complement and cells
Mechanism of Type III hyper.
immune complexes
Mechanism of Type IV hyper.
cell mediated immunity
Immunologic mediator for type I hyper
IgE (IgG in dogs)
Immunologic mediator for type II hyper
IgM, IgG
Immunologic mediator for type III hyper
IgM, IgG
Immunologic mediator for type IV hyper
T-lymphocytes
