Medicinal Plants Classification Biosynthesis and ... - Index of

Gastroprotective Triterpenoids: Pharmacological Mechanism
3.4.3. Proteinase-activated receptors (PAR)
There are four proteinases elucidated from today. PAR-1, PAR-3 and PAR-4 are
activated by thrombin, while PAR-2 is activated by trypsin or human mast cell tryptase.
PAR-2 is expressed in the gastrointestinal tract, including on epithelial cells and sensory
afferent neurons [87]. PARs are G protein-coupled receptor; those proteins are activated by
proteolytic unmasking of the N-terminal extracellular tethered ligand that presumably binds
to the extracellular loop 2 of the receptor itself [88]. PAR-2 agonist triggers mucus secretion
on stomach but not in duodenum and prevents gastric injury originate by HCl-ethanol or
indomethacin. PAR-2 triggers its cytoprotective secretion of gastric mucus by stimulating the
release of CGRP, due to capsaicin secretion abolished mucus secretion induced by PAR-2
[88].
Activation of PAR-1 releases VEGF (vascular endothelial growth factor) from platelets,
which promotes new blood vessels growth (angiogenesis); furthermore PAR-1 inhibits
release of endostatin an inhibitor of the growing of new blood vessels. The growth of new
blood vessels in the margin of ulcer helps to heal it [89].
3.3.4. LTB4 and leukocyte adherence
Leukocyte adherence contributes to the pathogenesis of gastric mucosal injury in two
ways. First, leukotriene B4 leads the increment on leukocyte adherence and at the same time
permits the liberation of oxygen-derived free radicals and proteases. Second, neutrophil
adherence to the vascular endothelium could obstruct capillaries, resulting in a reduction in
gastric mucosal blood flow and thereby predisposing the mucosa to injury [90]. Asako
studied the role of LTB4 in leukocyte adherence after indomethacin administration. In this
study, indomethacin induced the increment on leukocyte adherence; leukocyte adherence was
abolished after pretreatment with a LTB4 antagonist. Taking those results together suggest
that indomethacin induced gastric injury throw the increment on leukocyte adherence, a
dependent mechanism from the increment on LTB4 [91]. Furthermore, this appeared to be
mediated for the increment in the expression of intercellular adhesion molecule 1 (ICAM-1)
due to pretreatment with an antibody against ICAM-1 reduced leukocyte adherence and
susceptibility to NSAID-induce gastric damage [92].
Lately, the gastroprotective effect of many substances has been related with the
decrement on LTB4 production and leukocyte adherence at basal levels. NO, H2S, PGsderived
from COX-2 maintain basal leukocyte adherence levels. The attachment of NO and
H2S to the molecule of an NSAID, commonly named such as nitric-oxide releasing NSAIDs
and hydrogen sulfide-NSAID contributes to the decrement on gastric injury-induced by
NSAID. This diminish in gastric injury is by the decrement on LTB4 production and
leukocyte adherence [5, 24, 43]. Besides, lipoxins exerts their gastroprotective effect by the
reduction on leukocyte adherence in mesentery [14].
However, not all traditional NSAIDs cause gastric injury; recently, acemetacin, a prodrug
of indomethacin demonstrated to induce gastric safety against to its biotransformation to
indomethacin. Acemetacin induced inhibition of PGs as traditional NSAIDs but it did not
induce the increment on LTB4 or leukocyte adherence, then its gastric safety is related with
the lack on the increment on LTB4 and leukocyte adherence [15].
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