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Kallikrein - downstream pathway

Activation/ inhibition of Kallikrein?
Action of Kallikrein?

Activated by proteolytic enzymes released from cells by tissue damage.
A specific protease
- high molecular weight kininogen (blood) -> bradykinin
- low molecular weight kininogen (tissue) -> kallidin
[Also generates plasmin from plasminogen]

Natural inhibitor = C1 esterase inhibitor (C1-INH)
Artificial inhibitor = ecallantide (mimics antibody binding domain)

Bradykinin & kallidin activate constitutively expressed B2 receptors.
Removal of the C-terminal arginine (by kininase I) -> gives des-arg products

Des-arg products activate B1 receptors (induced by inflamation)

Further removal of C-terminal Phe (by kininase II aka ACE) causes complete inactivation
- thus ACE inhibitors cause BK levels to rise



Produced by cleavage of high molecular weight kininogen by kallikrein

Originally identified as a slow contractor of smooth muscle e.g in guinea pig ileum.

Induces vasodilatation
Activates B2 receptors


High molecular weight kininogen

Found in blood
Precursor of bradykinin
Cleaved by kallikrein


Low molecular weight kininogen

Found in tissues
Precursor of kallidin
Cleaved by kallikrein


B2 receptors

Effects on endothelium?

Constitutively expressed
Activated by bradykinin and kallidin

Gq couples -> release IP3, increasing [Ca]i.
- in endothelium: NO released diffuses short distance to arterial smooth muscle cells- causes relaxation, increasing blood flow (rubor & calor)


B1 receptors

Only expressed at low levels constitutively
- induced by inflammation
- suppressed by corticosteroids

Activated by des-arg products of kininase I cleavage of bradykinin and kallidin.

Drugs inhibiting binding of bradykinin have been developed but are not in clinical use.


Hereditary angioedema

Rare acute inflammatory condition characterised by episodes of severe (often painful) swelling.

Treated by kallikrein inhibitor Kalbitor



Identified as fast contractors of smooth muscle
- Substance P aka NK1
- Substance K aka NK2
- Neurokinin B aka NK3

Tachykinin receptors are Gq coupled- increase [Ca]i


Substance P

aka NK1
Prototypical tachykinin
Released from peripheral nerves (along with CGRP)
Causes neurogenic inflammation. May also be imp in migrane and asthma.



= high molecular weight peptides
Unlike many other inflammatory mediators are not stored, but produced on demand by gene transcription, released by vesicle shedding
- transcription is inhibited by glucocorticoids

Produced by T cells, macrophages, monocytes

Pro-inflammatory: IL-1, IL-2, IL-6, TNF-α.
Inhibit production of other cytokines: IL-4, IL-10.

TNF-α is particularly imp in rheumatoid arthritis.


Nerve growth factor (NGF)

Released from activated macrophages

Recently identified as potent agent causing pain in arthritis
- monoclonal antibody against NGF (tanezumab) has potent analgesic effects in osteoarthritis, but so effective that patients overused their damaged joint & exacerbated damage.


Membrane phospholipid structure

Fatty acid at 1 location on glycerol backbone is saturated
FA at 2 location is unsaturated, often arachidonic acid.

Cleaved by phospholipases at sites depending on the phospholipase.


Phospholipase A2 (PLA2)

Initiating event of production of inflammatory mediators from arachidonic acid.
Activation depends on both:
- rise in intracellular calcium
- activation of GPCRs such as B1 or B2 receptors- these activate downstream kinases which phosphorylate PLA2, switching it on.

Cleaves phospholipids at position 2- generates:
- arachidonic acid
- lyso-phosphatidylcholine (i.e the phospholipid lacking the position 2 fatty acid)

Also found in insect & snake venom- explaining the potent inflammatory action of snake bite


Arachidonic acid

Generated by PLA2 cleaving phospholipids
Unsaturated fatty acid, contains 4 cis double bonds at 5, 8, 11, 14 positions.

Many important inflammatory mediators are produced from arachadonic acid by COX enzymes or by 5, 12- or 15-lipoxygenase.
Products are collectively called eicosanoids. Include:
- 12-HETE (produced by 12-lipoxygenase)
- cyclic endoperoxides -> prostanoids (prostaglandins & thromboxanes)
- 5 HPETE -> leukotrienes



aka Hydroxyeicosatetraenoic acid
Produced from arachidonic acid by 12-lipoxygenase

Chemotactic messenger employed in the migration of leukocytes to site of injury



Produced by 5-lipoxygenase from arachadonic acid.
NB zileutin used clinically as a 5-lipoxygenase inhibitor

Produced predominantly by inflammatory cells e.g mast cells, macrophages.




- neutrophil and macrophage adherence, chemotaxis & proliferation
- cytokine production by macrophages & lymphocytes


Cysteinyl leukotrienes

Constrict coronary vessels but increase blood flow & vascular permeability elsewhere
Powerful spasmogens: constrict bronchilar smooth muscle

Imp in asthma & other inflammatory disorders.

Used in maintenance of asthma:
- zileuton = 5-lipoxygenase inhibitor
- zafirlukast is a specific cysteinyl leukotriene receptor antagonist


Platelet activating factor (PAF)
[a lipid compound]

Carboxylic acid linker at position one of phospholipid can be replaced by an ester bond:
- PLA2 removes 2-position FA from this precursor molecule
- another enzyme subsequently acetylates the 2 position
- result is PAF.

Extremely potent platelet aggregator
Chemotactic agent for leukocytes

Rapidly degraded in vivo by an acetyl hydroxylase which removes the 2-position acetyl group.



= prostaglandins & thromboxanes
Derived from arachidonic acid by COX enzymes.
Short lived mediators (~1 min) involved in many normal cellular functions as well as inflammatory reactions.

Inflammatory effects: swelling, fever, pain


COX enxymes

COX1 vs COX2?

Bi-functional, catalyse 2 distinct reactions

1) cyclo-oxygenase reaction leading to PG-G [inhibited by NSAIDS]

2) peroxidase reaction resulting in PGH2 (then processed by various downstream enzymes to produce different end-products)

COX1: constitutively expressed, involved in secretion of stomach acids & production of prostanoids in tissue
COX2: induced by inflammation


Inflammatory effects of prostanoids: Swelling

PGI2 (prostacyclin) acting on IP receptors

PGD2 acting on DP1 receptors -> increase in cAMP -> vascular smooth muscle relaxation -> increased blood flow


Inflammatory effects of prostanoids: Fever

PGE2 locally produced in the hypothalamus (probably in response to IL-2 secretion from leukocytes)
Acts locally on neurones via EP3 receptor -> decrease in cAMP


Inflammatory effects of prostanoids: Pain

PGE2 effects on EP2/4 receptors -> increase in cAMP -> enhances sensory fibre response to other painful signals (hyperalgesia)


Actions of prostanoids on blood vessels and in platelet aggregation

PGI2 produced by endothelial cells has vasodilatory & anti-aggregatory actions
TXA2 produced by platelets has vasoconstrictor & pro-aggregatory actions

In undamaged blood vessels, these actions are balanced & platelets do not aggregate. Endothelial damage alters balance in favour of platelet aggregation.

TXA3 derived from eicosapentaenoic acid (from fish oil) has lower pro-aggregatory actions- lower probability of thrombus.


Physiological actions of prostaglandins

-smooth muscle
- kidney
- stomach

Smooth muscle: contract or relax uterine, bronchial and GI smooth muscle

Kidney: regulate renin release & modify tubular reabsorption of sodium

Stomach: stimulate mucus & bicarbonate secretion that provides protection from acid attack, & inhibit acid secretion from parietal cells

Believed to enhance tumour growth in some cases, by inhibiting apoptosis, promoting invasion & stimulating angiogenesis (finding that COX inhibitors reduce growth rate of colon carcinomas)