Chronic Inflammation

Question 1

What is chronic inflammation?

Answer 1

Response of prolonged duration in which inflammation, tissue injury and attempts at repair coexist in varying combinations

Question 2

What are the 3 major categories for causes of chronic inflammation?

Answer 2

Question 3

What is the disease burden of chronic inflammation (i.e. epidemiology)?

Answer 3

Most significant cause of death in world

3/5 people die as a result of chronic inflammatory condition

• Diabetes
• CVD
• Arthritis
• COPD
• Allergies/asthma

Question 4

Compare and contrast acute and chronic inflammation with respect to:

• Causative agent
• Cellular infiltrate
• Primary mediators
• Onset
• Duration
• Outcomes

Answer 4

Question 5

TNF

• Secreted by what cells?
• Has what actions?
• Secreted in acute or chronic inflammation?

Answer 5

• Macrophages, mast cells, t-cells
• Stimulate expression of endothelial cell adhesion molecules and secretion of other cytokines; systemic effects
• Acute

Question 6

IL-1

• Secreted by what cells?
• What effects does this have on the body?
• Secreted in acute or chronic inflammation?

Answer 6

• Macrophages, endothelial cells
• Similar to TNF, greater role in prompting fever @ hypothalamus
• Acute

Question 7

IL-6

• Secreted by what cells?
• What effects does it have on body?
• Secreted in acute or chronic inflammation?

Answer 7

• Macrophages
• Systemic effects during acute phase response
• Acute

Question 8

Chemokines

• Secreted by what cells?
• What is their effect on body?
• Secreted in acute or chronic inflammation?

Answer 8

• Macrophages, endothelial cells, T cells, mast cells
• Recruitment of leukocytes to sites of inflammation, migration of cells in normal tissue
• Acute

Question 9

IL-17

• Secreted by what cells
• What is the effect this has on the body?
• Secreted in acute or chronic inflammation?

Answer 9

• T-cells
• Recruitment of neutrophils and monocytes
• Acute and chronic

Question 10

IL-12

• Secreted by what cells?
• Has what actions in the body?
• Secreted in acute or chronic inflammation?

Answer 10

• Dendritic cells, macrophages
• Increased production of INF-gamma
• Chronic

Question 11

INF-gamma

• Secreted by what cells?
• What are actions in body?
• Secreted in acute or chronic inflammation?

Answer 11

• T-cells, NK cells
• Activation of macrophages
• Chronic

Question 12

What are the morphologic features of chronic inflammation when visualized in histological staining?

Answer 12

Question 13

Macrophages can have actions that are both beneficial to cells and detrimental to cells. Describe these different effects on cells from the actions of macrophages.

Answer 13

(+)

• Communicate with t-cells (APC and respond to signals from t cells)
• Secrete inflammatory mediators
  
  • TNF
  • IL-1
  • Chemokines
• Ingest/eliminate microbes and dead tissue
• Initiate tissue repair process

(-)

• Cycle of elimination can be inappropriately/excessively activated leading to tissue damage beyond what is necessary to address original insult to tissue

Question 14

What are the 2 types of macrophages activation?

Compare and contrast these mechanisms of activating macrophages.

Answer 14

Classical / M1 –> activated in acute inflammation

• Pro-inflammatory
• PAMPs and DAMPs –> PRRs (TLRs and NOD like receptors) on resident dendritic cells or invading macrophage –> consume antigen –> present to T cell –> T cell matures and secretes INF-gamma –> activate macrophages to phagocytose invading microbe / damaging substances and generate NO + ROS to degrade/inactivate/kill them

Alternative / M2 –> activated after classical

• Anti-inflammatory
• Key cytokines are IL-4 and IL-13
• Does not result in microbicidal macrophages
• Inhibits classical pathway
• Results in tissue repair
• Microbes secrete growth factors that promote:
  
  • angiogenesis
  • activation of fibroblasts
  • collagen synthesis

Question 15

Normally we think of lymphocytes (t cells and b cells) as having a beneficial effect on inflammation b/c they amplify the response and mediate the adaptiave arm of the immune response. When are these cells considered to actually have destructive effects?

Answer 15

When activated in chronic inflammation the inflammation tends to be persistent and severe so they become over stimulated and promote the persistent inflammatory response.

Question 16

• Let’s say that we have a macrophage that has been classically activated by INF-gamma. What is the cycle of inflammation that it perpetuates to keep the process going?
• How is this process “turned off”?

Answer 16

Macrophage can

• Present antigen to t cells –> t cell becomes activated (Th1 if intracellular, Th17 if extracellular) –> T cell secretes other cytokines that lead to additional leukocyte recruitment and enhanced inflammation –> T cell could also secrete more INF-gamma to activate more macrophages
• Activated macrophage can secrete TNF and IL-1 which will promote additional leukocyte recruitment and inflammation
• Process is turned off by removal of the offending stimuli

Question 17

Complete this table.

Answer 17

Question 18

What are the 2 different kinds of chronic inflammation?

Answer 18

Question 19

What are some examples of chronic, granulomatous inflammation that are:

• Non-caseating
• Caseating

Answer 19

Question 20

Let’s say that a tissue is damaged from inflammation. What 2 processes does that tissue go through to repair itself?

Answer 20

Question 21

In order for damaged tissue to regenerate, what must be true of that tissue?

Answer 21

It must possess labile stem cells that are capable of proliferating and differentiating to replace the damaged cells. Tissue that does not have this capacity or has a lesser degree of this capacity will undergo scar formation when damaged.

Question 22

What are the 3 steps of scar formation?

Answer 22

Question 23

Complete this table.

Answer 23

Question 25

Describe the basic overview of what happens during angiogenesis and the signaling mediators that are involved.

Answer 25

Vasodilaton occurs during inflammation. During this process, growth factors (VEGF, and NOTCH signaling) promote sprouting of “leading tip” cells. Pericytes are recruited to expand the budding tip and when the tips come in contact with another tip cell they bind to one another through integrins and develop into a vascular stalk which then becomes a new blood vessel. While all of this is happening, matrix metalloproteinases are degrading the ECM to allow for this remodeling and extension of the vascular network.

Question 26

What is the role of fibroblasts in scar formation and tissue repair?

Answer 26

Fibroblasts migrate to the site of injury, proliferate, and lay down ECM proteins needed to rebuild the tissue’s structure.

Question 27

What is the role of TGF-beta and M2 macrophages in tissue repair?

Answer 27

M2 macrophages secrete TGF-beta, which promotes the migration and proliferation of fibroblasts, promotes the synthesis of collagen and fibronectin in fibroblasts, and inhibits the degradation of the ECM by MMPs.

Question 28

What is the difference between primary and secondary intention with regards to cutaneous wound healing?

Answer 28

Question 29

What allows for recovery of tensile strength of the tissue following wound healing?

Answer 29

Collagen synthesis > collagen degradation

Structural modifications of collagen fibers (cross-linking that happens during wound healing, increase in fiber size)

*Even at best, scar is only ~80% as strong as original tissue*

Question 30

What is the difference between fibrosis and fibroblast activity that occurs as part of scar formation?

Answer 30

Question 31

For each image, what is the:

• type of abnormal wound healing displayed?
• Some examples of conditions?

Answer 31