Tobias chapter 1 - Inflammatory Response

Question 1

What factors are responsible for the activation of the intrinsic and extrinsic pathways of coagulation? What triggers the activation of each factor?

Answer 1

Intrinsic: factor XII (Hageman factor) contacting a negatively charged surface.

Extrinsic: factor VII contacting subendothelial tissue factor.

Question 2

Coagulation is a predominantly pro-inflammatory process. How does thrombin mediate inflammation?

Answer 2

Activates endothelial protein-activated receptors, promoting the synthesis of prostaglandins, nitric oxide and platelet derived growth factor (PDGF).

Question 3

Briefly describe the structure and function of the Kallikrein-Kinin System

Answer 3

System composed of several classes of vasodilatory proteins (Kalikrein, kininogens and Kinins) produced in the liver.
Connected to the coagulation system. When prekallikrein and kininogen contact a negative charged surface, they activate factor XII (Hagen factor, intrinsic pathway activator), which converts prekallikrein into kallikrein. Kallikrein cleaved kininogens into kinins, stimulating further activation of factor of XII (self perpetuating process) .

Question 4

Bradykinin is the most notable kinin, and acts in B1 and B2 receptors. Discuss the function of these receptors.

Answer 4

B2 are ubiquitous and constitutively expressed and healthy tissue, and responsible for the homeostatic effects of bradykinin.

B1 are produced in pathologic conditions. Nuclear factor Kappa B (NFkB) plays an integral role in B1 receptor induction and regulation within the M1 macrophage. Acting on this receptor, bradykinin mediates endothelial prostacycline synthesis, super oxide formation, and tissue plasminogen release.
Effects: stimulates venous dilation through NO release, increases vascular permeability and enhances pain response.

Question 5

what is the primary tachikinin? list some of its effects

Answer 5

Substance P
Binds to NK-Rs receptors, leading to:
Transmission of pain and pro-inflammatory signals
Induces release of prostaglandins
Vasodilation
Synthesis of leukotriens
Stimulates leukocyte chemotaxis and endothelial adhesion, promoting extravasation.

Question 6

Answer 6

Question 7

Answer 7

Question 8

Contrast the lifespan of monocytes to that of macrophages.

Answer 8

If not stimulated by an inflammatory process, monocytes have a very short useful life. By contrast, macrophages can persist in tissues for months to years, fulfilling an important function as antigen-presenting cells to lymphocytes. 

Question 9

Contrast the function of M1 and M2 macrophages

Answer 9

M1: activated by infectious agents or pro-inflammatory cytokines (TNF alpha). Debridement, phagocytosis, removal of damaged cells. produce inflammatory cytokines (IL-1 beta, IL-6 and TNF alpha) and prostaglandins. Secrete collagen and elastics facilitating phagocytosis.

M2: activated in response to inflammatory cytokines (IL – 4; IL – 13; IL – 10). Secrets, PDF or TGF – beta, stimulating fibroblasts to produce collagen and dampening the inflammatory response. secrete collagen and elastosis facilitating remodeling. 

Question 10

Contrast the origin and function of tissue-resident macrophages, and monocyte-derived macrophages 

Answer 10

Tissue macrophages are constitutively present, sentinel cells that arise early in embryogenesis, independent of monocytes. Tissue-resident macrophages are responsible for early recognition of inflammatory stimuli and are a major, early source of proinflammatory cytokines.

Circulating monocytes can extravasate in response to chemotaxins, including cytokines, fibronectin, elastin, complement factors (C3a, C5a), thrombin, and growth factors (e.g., platelet-derived growth factor [PDGF], transforming growth factor-beta [TGF-β]).21 Once in the tissue, monocytes can differentiate into macrophages and reside in the provisional fibrin-based extracellular matrix at a site of inflammation.21,106 Monocyte-derived macrophages can constitute the main macrophage type in inflammatory conditions. In addition to their production of macrophages, monocytes serve as short-lived effector cells that promote vascular regrowth in tissues.14

Question 11

What happens to neutrophils once they exert their phagocytic/bactericidal function? What is the timeline for this process?

Answer 11

Within 24 to 48 hours neutrophils undergo necrosis, apoptosis or are sloughed from the wound bed. Next, they are phagocytosed by macrophages, which begin to secrete anti-inflammatory mediators to blunt the inflammatory response and attract fibroblasts via chemokines.

Question 12

What do tertiary neutrophil granules contain? What is their fundamental importance?

Answer 12

Tertiary granules contain preformed receptors. They are important for converting inactive neutrophils into active cells in an inflammatory environment as part of the two-stage activation process.

Question 13

What do secondary neutrophil granules contain?

Answer 13

metalloproteinases

Question 14

Describe the two-stage process undergone by neutrophils in an inflammatory environment.

Answer 14

1)Stimulation by bacterial byproducts, cytokines, and chemokines mobilizes tertiary granules and secretory vesicles, increasing cell surface receptors.
2)De novo expression of receptors and cytokines

Question 15

Name four pro-inflammatory cytokines produced by neutrophils

Answer 15

IL-1-α
IL-1-β
IL-6
TNF-α

Question 16

What is the main neutrophil granule, and what does it contain?

Answer 16

Large axyrophil granule
Contains microbicidal peptides like myeloperoxidase, defensins, lysosome hydrolases, and neutral proteases.

Question 17

What are neutrophil extracellular traps? What is their function?

Answer 17

Cell-free DNA and other peptides (histones) that trap microorganisms and ensure a high local concentration of granular destructive enzymes. Also promotes clotting through platelet-dependent and independent mechanisms.

Question 18

What cell population peaks in the first 24-48 following injury? What drives these cells to the site of injury?

Answer 18

Leukocytes
Driven by chemoattractants (cytokines, complement byproducts, bacterial byproducts

Question 19

How do leukocytes “know” where to go after the extravasation process?

Answer 19

Leukocytes migrate along chemical gradients of exogenous (bacterial byproducts) and endogenous (complement components and chemokines) substances. They follow fibrin and fibronectin strands (matrix), secreting degradative enzymes that aid in directed movement.

Question 20

What is the function of ICAM-1?

Answer 20

Intercellular Adhesion Molecule (ICAM-1) - The most important endothelial cell integrin is responsible for the firm adherence of leukocytes to endothelial cells.

Question 21

What is the function of endothelial selectins and leukocyte ligands?

Answer 21

Responsible for leukocyte margination and rolling.

Question 22

What is the function of PECAM-1? Where is it found?

Answer 22

Platelet-Endothelial Cell Adhesion Molecule (PECAM-1). Found in endothelial cells. Facilitates leukocyte transendothelial migration and passage through the basement membrane.

Question 23

Referring to leukocyte extravasation, where does diapedesis primarily occur? (which kind of blood vessel). What endothelial process/structure facilitates this process?

Answer 23

Postcapillary venules

Facilitated by endothelial cell retraction and cell adhesion molecules.

Question 24

Name the two ways plasma products, small and large, can leave blood vessels.

Answer 24

Transcytoplasmic channels (small products)
Interendothelial gaps (large products)

Question 25

What is the primary purpose of vascular stasis?

Answer 25

Allows increased contact time among erythrocytes, leukocytes, and the vascular endothelium, leading to the next stage of acute inflammation

Question 26

Name the four phases of acute inflammatory response.

Answer 26

1) Vasodilation (briefly preceded by vasoconstriction)
2) Increased vascular permeability
3) Stasis/Margination
4) Leukocyte extravasation

Question 27

Transcytoplasmic channels (vesiculovacuolar organelles) - Name two vasoactive amines responsive to their creation and briefly describe their importance and limitations.

Answer 27

Histamine and serotonin

Allows the transcytosis of plasma products to the site of inflammation but does not allow the passage of large plasma molecules and mediators. These require interendothelial gaps.

Question 28

Name the following substances responsible for vasodilation following the initial vasoconstriction
1) Gaseous agent (1)
2) Vasoactive Amine (1)
3) Eicosanoid (2)
4) Component of the innate immune system

Answer 28

1) Nitric Oxide
2) Histamine
3) Leukotrienes and Prostaglandins
4) Complement

Question 29

Name or give an example of each of the following agents responsible for vasoconstriction following injury
1) Catecholamine (1)
2) Vasoactive Amines (2)
3) Kinin (1)
4) Eicosanoid (1)

Answer 29

1) Norepinephrine
2) Histamine and Serotonin
3) Bradykinin
4) Prostaglandin

Question 30

Answer 30

Question 31

Answer 31