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Infection and Immunity > Proteases + RONs > Flashcards

Proteases + RONs Flashcards

1
Q

what do proteases derive from?

A

plasma zymogens

tissue cells

activated leucocytes

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2
Q

central role of proteases

A

host defence

removal of damaged tissue

initiating repair

inflammation

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3
Q

plasma proteases - kinins (bradykinins)

A

vasodilation

increased permeability

pain

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4
Q

plasma proteases - complement

A

leucocyte activation, chemotaxis (C5)

mast cell degranulation (C3a, C5a)

bacterial opsonisation and lysis (C3b, C5-C9 complex)

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5
Q

clotting cascade

A

thrombosis, platelet activation

activates kinin and complement pathways

=> AMPLIFICATION

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6
Q

families of proteolytic enzymes

A
  1. matrix metalloproteinases (MMP)
  2. serine proteinases
  3. cysteine proteinases
  4. aspartate proteinases
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7
Q

types of MMP

A

MMP-1,-8,-13 -> collagenases

MMP-2 -> gelatinase A

MMP-3 … 28

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8
Q

roles of MMP

A

major class of enzymes that degrade cartilage

break down collagen and other membrane proteins

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9
Q

optimum pH for MMP

A

neutral

contain and require Zn2+

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10
Q

what inhibits MMPs?

A

TIMPS

= tissue inhibitors of metallo-proteinases

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11
Q

role of serine and cysteine proteinases

A

[break down matrix proteins]

-elastin
-laminin
-chondroitin sulfate + proteoglycans
-involved in antibody processing

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12
Q

optimum pH for serine and cysteine proteinases

A

neutral

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13
Q

what inhibits serine and cysteine proteinases?

A

serpins

= serine protease inhibitors

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14
Q

what inactivates serpins?

A

oxidation

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15
Q

proteases in inflammation

A

mucus cleavage - microbial invasion

Ig cleavage - dys-regulated immunity

leucocyte infiltration

tight junction regulation - leaky barrier; plasma extravasation

apoptosis

PAR activation - pain; inflammation

matrix remodelling - cell invasion, leucocyte migration

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16
Q

proteases in Rheumatoid arthritis

A

Cartilage proteoglycans (matrix material) lost rapidly
- Shock absorption impaired
- Loss of joint function; pain

Proteoglycans have open structure
- Highly accessible
- Sensitive to breakdown by several
proteinases

Collagen lost more slowly
- Causes ‘loss of function’ of cartilage as
smooth surface
- Broken down by MMPs (collagenases)

17
Q

Proteases in Multiple Sclerosis (MS)

A

High levels of MMPs detected in MS

BBB breakdown

Enhance leucocyte infiltration

Myelin and axonal damage

Formation of immunogenic myelin peptides

18
Q

which part of the MMP structure is most important?

A

C terminus -> substrate specificity and regulation

19
Q

what activates MMPs?

A

Removal of pro-peptide by other proteases - e.g. elastase or plasmin

Chemical modification of pro-peptides by RONS

Activate site of Zn2+ targeted by hydroxamate series of MMP inhibitors

20
Q

Use of synthetic MMP inhibitors in inflammation - PEPTIDOMIMETICS

A

Small hydroxamic acid-based molecules
- Zinc binding
- Based on collagen structure
- Effectively inhibit MMP activity

Lack specificity
- Act on most metalloenzymes

Non-peptide hydroxamates
- Better selectivity

No clinically useful drugs

21
Q

Protease inhibitors as drug therapies

A

MMP inhibitors

Serine and cysteine protease inhibitors
- On-going trials in cancer and
angiogenesis
- Some trials in arthritis and autoimmune
disease

Neutrophil elastase inhibitors for inflammatory lung disease (e.g. sivelistate, brensocatib)

22
Q

Other approaches to inhibiting MMPS

A

Tetracycline derivatives (sub-antibiotic dose)
- Reduce MMP synthesis and activity
- Doxycycline (periostat) used for
treatment of periodontal and skin disease

Monoclonal antibody-based therapeutics
- High specificity for individual MMPs

Endogenous inhibitors of MMPs
- TIMPs (tissue inhibitors of
metalloproteinase) are difficult drugs
- Upregulation of synthesis?
- Limited selectivity?

23
Q

what are RONS?

A

reactive oxygen and nitrogen species

24
Q

how are RONS produced? + equations

A

infiltrating leucocytes and tissue resident cells

NADPH catalyses formation of superoxide (O2-)
- O2- dismuted to form peroxide (H2O2)

H2O2 further metabolised to form…
- Hydroxyl radical (OH-)
- Hypohalous acids - e.g. HClO => H+ ClO-

H2O2 inactivated catalase

Reactive nitrogen species formed from NOS-derived NO combining with oxygen species

25
Q

what do leucocytes phagocytose?

A

bacteria

yeast

immune complexes

damaged tissue

26
Q

effect of RONS

A

Lipid peroxidation

Proteins oxidation

DNA damage

Cell apoptosis and necrosis

Affect cell signaling

27
Q

regulation of proteases by RONS

A

[Amino acid modifications]

Inactivation of serpins

Modification of latent MMPs => activation

28
Q

Reactive oxygen species and joint damage

A

Rheumatoid synovial tissue undergoes cycles of hypoxia and reperfusion - oxidative stress

Immune complex formation in some diseases

Generation of superoxide and RONS
- Tissue injury
- Modulation of cell function

29
Q

Anti-inflammatory actions of dietary anti-oxidants in Rheumatoid Arthritis

A

Clinical trials involving administration of two 250mg capsules of pomegranate extract to RA patients for 8 weeks

Resulted in reduction in disease activity score, join swelling and pain severity

30
Q

RONS in MS

A

BBB disruption

Leucocyte migration

Promote pro-inflammatory activity in resident CNS cells

Oligodendrocyte cell death

31
Q

Anti-inflammatory actions of antioxidants in MS

A

Decreased antioxidant status

Use of dietary anti-oxidants

Conflicting results

Lipoic acid in treatment of MS

Infection and Immunity (17 decks)

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