Proteases, reactive oxygen and nitrogen species

Question 1

What are proteases derived from?

Answer 1

Plasma zymogens, tissue cells and activated leukocytes.

Question 2

What do proteases have a central role in?

Answer 2

Host defence, removal of damaged tissue, initiating repair and inflammation.

Question 3

What effect do kinins have?

Answer 3

They cause vasodilation, increased permeability and pain.

Question 4

What is the complement?

Answer 4

A larger protein consisting of 10 amino acids.

Question 5

What does the complement system cause?

Answer 5

Leukocyte activation, chemotaxis, mast cell degranulation, bacterial opsonisation and lysis.

Question 6

What are plasma proteases activated by?

Answer 6

Tissue injury, antibody complexes and foreign surfaces.

Question 7

What do the complement components assemble to form?

Answer 7

A pore that helps to lyse target cells.

Question 8

What is the C3b component of the complement important in?

Answer 8

It is a ligand for integrins on the neutrophil surface - it has a dual function.

Question 9

What is thrombosis?

Answer 9

The generation of clotting factors via the protease cascade.

Question 10

What is the clotting cascade important in?

Answer 10

Thrombosis, platelet activation and activating kinin and complement pathways.

Question 11

What is angioedema?

Answer 11

Deep cutaneous and musosal swelling of the lips, tongue, larynx GI that lasts for days.

Question 12

What is urticaria?

Answer 12

An outbreak of swollen, pale red bumps that appear on the skin suddenly. Angioedema is a form of this.

Question 13

What is the cause of angioedema?

Answer 13

Mast cell degranulation.

Question 14

How can angioedema be treated?

Answer 14

H1 antagonists.

Question 15

What are some of the other forms of angioedema?

Answer 15

Histamine-independent forms such as drug induced or hereditary.

Question 16

What are some of the causes of hereditary angioedema that have been identified?

Answer 16

Several gene defects such as increased complement or bradykinin activation resulting in a decrease in protease inhibitors and increased kininogenase.

Question 17

What can hereditary angioedema be treated with?

Answer 17

Exogenous C1 inhibitor and bradykinin receptor antagonist.

Question 18

What is an example of a bradykinin receptor antagonist?

Answer 18

Icatibant.

Question 19

How are can angioedema be induced?

Answer 19

Induced by angiotensin converting enzyme inhibitor (ACE).

Question 20

How can drug induced angioedema be caused?

Answer 20

ACE inhibitors block ANGII synthesis, which is useful in hypertension, but they block bradykinin degradation

Question 21

What happens if ACE inhibitors are used in patients?

Answer 21

There will be elevated levels of bradykinin which will result in increased inflammation, as bradykinin is usually inactivated by ACE.

Question 22

Why are ACE inhibitors used to lower blood pressure?

Answer 22

ACE is responsible for metabolising angiotensin 1 to 2, which elevates blood pressure - blocking this can decrease blood pressure.

Question 23

What happens if an animal is immumised against specific collagen?

Answer 23

You can induce a type of arthritis.

Question 24

What are the families of proteolytic enzymes?

Answer 24

MMP, serine proteinases, cysteine proteinases and aspartate proteinases.

Question 25

What is cartilage made up of?

Answer 25

Collagen and proteoglycans.

Question 26

What happens to tissue in rheumatoid arthritis?

Answer 26

Cartilage proteoglycans are lost rapidly so there is loss of joint function and resulting pain.

Question 27

What happens to proteoglycans in rheumatoid arthritis?

Answer 27

As they have an open structure they are highly accessible and therefore sensitive to breakdown by several proteinases.

Question 28

What happens to collagen in rheumatoid arthritis?

Answer 28

It is lost more slowly than proteoglycan, but causes the loss of function of cartilage as a smooth surface. It is broken down by MMPs (collagenases).

Question 29

What are matrix metalloproteinases?

Answer 29

MMP - they break down collagen and other matrix proteins. They are a major class of enzymes that degrade cartilage.

Question 30

What conditions do MMPs need to function?

Answer 30

They are active at neutral pH and contain and require Zn2+ ions.

Question 31

What are MMPs inhibited by?

Answer 31

Tissue inhibitors of metallo-proteinases, TIMPs.

Question 32

What is the usual balance between MMPs and TIMPs?

Answer 32

There is usually a balance to provide a turnover to repair for restoration. If this balance is wrong there is tissue damage.

Question 33

What is the domain structure of MMP?

Answer 33

There is a propeptide, catalytic, hinge and C-terminal region.

Question 34

What is MMP activated by?

Answer 34

Removal of propeptide by other proteases such as elastase or plasmin and chemicla modification of propeptide by RONS.

Question 35

What is the C-terminus of MMP important in?

Answer 35

Substrate specificity and regulation.

Question 36

What drugs can be used in inflammation?

Answer 36

Synthetic MMP inhibitors.

Question 37

What are peptidomimetics?

Answer 37

Small hydroxamic acid-based molecules based on collagen structure. They are effectively used to inhibit MMP activity, but lack specificity and act on most metalloenzymes.

Question 38

What can tetracycline derivatives be used for?

Answer 38

Reducing MMP synthesis and activity - doxycycline is used for the treatment of periodontal and skin disease.

Question 39

What are serpins?

Answer 39

Serine protease inhibitors.

Question 40

What are serpins inactivated by?

Answer 40

Oxidation.

Question 41

What proteinases break down matrix proteins?

Answer 41

Elastin, laminin, chondroitin sulfate and proteoglycans.

Question 42

What are some of the adverse effects of MMP inhibitors?

Answer 42

Musculoskeletal syndrome, lack of specificity.

Question 43

What are reactive oxygen and nitrogen species (RONS) produced by?

Answer 43

Infiltrating leukocytes and tissue resident cells.

Question 44

What is H2O2 inactivated by?

Answer 44

Catalase.

Question 45

What does NADPH catalyse the formation of?

Answer 45

Superoxide.

Question 46

What is H2O2 metabolised to form?

Answer 46

Hydroxyl radical OH-, hypohalous acids such as HClO.

Question 47

What is respiratory burst?

Answer 47

When leukocytes phagocytose and release reactive oxygen species.

Question 48

What is hypoxia?

Answer 48

A condition when the body is deprived of adequate oxygen supply at tissue level.

Question 49

How do oxidant levels vary in rheumatoid arthritis patients?

Answer 49

There is increased oxidant and decreased antioxidant levels - a disturbed balance in inflammatory diseases.

Question 50

What effects do RONS cause?

Answer 50

They activate inflammatory gene transcription (NFKB, further inflammation), they cause amino acid modifications, matrix modifications, DNA damage and cell apoptosis and necrosis.

Question 51

What amino acid modifications occur due to RONS?

Answer 51

Inactivation of serpins, modification of latent MMPs, making host proteins immunogenic.

Question 52

Was there an association between disease and antioxidant intake found in studies?

Answer 52

No - no association.