Current Drug Targets – Immune, Endocrine & Metabolic Disorders Volume 3, No. 1, 2003
Contents
Controlled Modulation of Inflammatory, Stress
and Apoptotic Responses in Macrophages Pp. 1-22
I.
Yu. Malyshev and A. Shnyra
Unfolding the Pathophysiological Role of
Bioactive Lysophospholipids
Pp. 23-32
Yan
Xu, Yi-jin Xiao, Kui Zhu, Linnea M. Baudhuin, Jun Lu, Guiying Hong, Kwan-sik
Kim, Kelly L. Cristina, Li Song, Freager S. Williams, Paul Elson, Maurie
Markman and Jerome Belinson
Studies on Human Neutrophil Biological
Functions by Means of Formylpeptide Receptor Agonists and Antagonists Pp. 33-42
A.
Dalpiaz, S. Spisani, C. Biondi, E. Fabbri, M. Nalli and M.E. Ferretti
Vitamin D Analogs- Drug Design Based on
Proteins Involved in Vitamin D Signal Transduction Pp. 43-66
Sonoko
Masuda and Glenville Jones
Pathobiology of Cholesterol Gallstone
Disease: From Equilibrium Ternary Phase Diagram to Agents Preventing
Cholesterol Crystallization and Stone Formation Pp. 67-81
Piero
Portincasa, Antonio Moschetta, Giuseppe Calamita , Antonio Margari and Giuseppe Palasciano
WISH Cells as a Model for the “In Vitro”
Study of Amnion Pathophysiology
Pp. 83-92
B.
Pavan,
Abstracts
[Back to top] Controlled Modulation of Inflammatory, Stress
and Apoptotic Responses in Macrophages
I.
Yu. Malyshev and A. Shnyra
An outstanding
question of current immunology is to define the mechanisms by which microbial
products influence the immunopathologic host response elements in the early
stages of infection. Macrophages are now well recognized to have a critical
role in both innate and acquired immunity. In order to adjust promptly to
continuous changes in microenvironment and maintain the immunologic balance,
macrophages adequately respond by activating one of the numerous immunologic
programs. However, sustained macrophage activation and excessive production of
inflammatory mediators can perpetuate the numerous pathological processes and
contribute to induction of stress response and even apoptosis. Therefore,
selective modulation of macrophage activity represents an important strategy
for prevention and treatment of inappropriate inflammatory responses in order
to minimize the unwanted side-effects of the immunity. Macrophages can be
selectively reprogrammed for a specific phenotype of immune response, e.g.
cytokine or nitric oxide (NO), by relatively short-term exposure of the cells
to substimulatory concentrations of different microbial components, including
LPS. These LPS-dependent reprogramming effects are mediated by IFNgamma-
independent autocrine cytokine regulatory mechanisms that also controlled at
the transcriptional level. Furthermore, LPS reprogrammed macrophages exhibit
differential capacity to resist experimentally induced apoptosis and to produce
heat shock proteins. Complete analysis of, and appreciation for, the
immunoregulatory mechanisms implicated in LPS-dependent reprogramming of immune
responses in macrophages can be expected to increase our understanding of the
host innate response, as well as allow investigators to utilize emerging
immunologic technologies in effective treatment of infections and chronic
inflammatory diseases.
[Back to top] Unfolding the Pathophysiological Role of
Bioactive Lysophospholipids
Yan
Xu, Yi-jin Xiao, Kui Zhu, Linnea M. Baudhuin, Jun Lu, Guiying Hong, Kwan-sik
Kim, Kelly L. Cristina, Li Song, Freager S. Williams, Paul Elson, Maurie
Markman and Jerome Belinson
Lysophospholipids
(LPLs), including glycerol- and sphingoid-based lipids, stimulate cell
signaling and play important pathophysiological roles in humans and other
animals. These LPLs include lysophosphatidic acid (LPA),
lysophosphatidylinositol (LPI), lysophosphatidylcholine (LPC),
lysophosphatidylserine (LPS), sphingosine-1-phosphate (S1P), and
sphingosylphosphorylcholine (SPC). Analyses of LPLs in human body fluids from
subjects with different pathophysiological conditions reveal not only the
relevance of LPLs in human diseases, but also their potential application as
biomarkers and/or therapeutic targets. In recent years, the identification
and/or characterization of the plasma membrane receptors for LPLs and enzymes
regulating the metabolism of LPLs have greatly facilitated our understanding of
their role and signaling properties. In vitro and in vivo functional and
signaling studies have revealed the broad and potent biological effects of LPLs
and the mechanisms of LPL actions in different cellular systems. Development of
specific antagonists for each of the LPL receptors will provide powerful tools
for dissecting signaling pathways mediated by receptor subtypes. More
importantly, these antagonists may serve as therapeutics for relevant diseases.
Genetic depletion of LPL receptors in mice has provided and will continue to
provide critical information on the pathophysiological roles of LPL receptors.
It is important to further evaluate the significance of targeting these
bioactive LPL receptors, their downstream signaling molecules, and/or metabolic
enzymes in the treatment of cancers and other diseases.
[Back to top] Studies on Human Neutrophil Biological
Functions by Means of Formylpeptide Receptor Agonists and Antagonists
A.
Dalpiaz, S. Spisani, C. Biondi, E. Fabbri, M. Nalli and M.E. Ferretti
Phagocytes are
activated by several extracellular signals, including formylpeptides derived
from bacterial proteins or disrupted cells. The most intensely studied
member of the formylpeptide
family is the synthetic tripeptide N-formyl-L-methionyl-L-leucyl-Lphenylalanine
(fMLP), whose specific receptors have been identified on neutrophil plasma
membrane and subsequently cloned. The fMLP-receptor interaction activates
multiple transduction pathways responsible for various neutrophil functions
such as adhesion, chemotaxis, exocytosis of secretory granules and superoxide
anion production, which represent the physiological response to bacterial
infection and tissue damage. An unresolved question is whether signaling
requirements are identical or specific for each physiological function. The
development of fMLP receptor agonists and antagonists has led to an improvement
of our knowledge about the above issue. Of particular interest is the possibility
that receptorial antagonists, able to transiently inhibit neutrophil responses
to formylpeptides, could be therapeutic agents in the treatment of
inflammation-related diseases.
Aim of this review is,
i) to summarise the current understanding of the series of events that begins
at the level of formylpeptide-receptor interaction and is responsible for the
activation of transduction pathways, which finally determine neutrophil
response; ii) to define the state of art regarding the synthesis as well as the
biological actions of fMLP receptor agonists and antagonists.
[Back to top] Vitamin D Analogs- Drug Design Based on
Proteins Involved in Vitamin D Signal Transduction
Sonoko
Masuda and Glenville Jones
Vitamin D analogs have
proven to be very valuable tools for the treatment of calcium-related diseases
and certain hyperproliferative conditions such as renal osteodystrophy,
psoriasis and cancer. In general, vitamin D analogs exploit the enzymic and
receptor machinery of the 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3)
signal transduction pathway. Key proteins in this cascade include the vitamin D
receptor (VDR), the vitamin D-binding protein (DBP) and three cytochrome P450s
(CYP27A, CYP27B and CYP24) which effect the synthesis and breakdown of the
natural hormone, 1α,25(OH)2D3. Analogs have been
designed which reduce or enhance the importance of each of these proteins in
the signal transduction pathway. Vitamin D prodrugs require one or more steps
of activation and overcome congenital or acquired blocks in the
1α-hydroxylation step. By far the biggest class of vitamin D analogs are
the VDR agonists which directly mimic 1α,25(OH)2D3
and trigger protein conformational changes in the receptor which lead to
changes in the transcriptional machinery at vitamin D-responsive genes. Other
emerging classes of molecules include the VDR antagonists and CYP24 inhibitors
which target different events in the cascade. This review assesses the relative
importance of each of the proteins of the vitamin D cascade, evaluates the
success of these modifications in tailoring drugs in all classes for selected
disease states and contemplates future directions for the field.
[Back to top] Pathobiology of Cholesterol Gallstone
Disease: From Equilibrium Ternary Phase Diagram to Agents Preventing
Cholesterol Crystallization and Stone Formation
Piero
Portincasa, Antonio Moschetta, Giuseppe Calamita , Antonio Margari and Giuseppe Palasciano
The primum movens in
cholesterol gallstone formation is hypersecretion of hepatic cholesterol,
chronic surpersaturation of bile with cholesterol and rapid precipitation of
cholesterol crystals in the gallbladder from cholesterol-enriched vesicles.
Associated events
include biochemical defects (increased biliary mucin, and increased proportions
of hydrophobic bile salts in the intestine and gallbladder), motility defects
(gallbladder smooth muscle hypocontractility in vitro and gallbladder stasis in
vivo, sluggish intestinal transit), and an abnormal genetic background.
The study of
physical-chemical factors and pathways leading to cholesterol crystallization
in bile has clinical relevance and the task can be carried out in different
ways. The lithogenicity of bile is investigated in artificial model biles made
by three biliary lipids – cholesterol, bile salts and phospholipids – variably
combined in systems plotting within the equilibrium ternary phase diagram;
also, crystallization propensity of ex vivo incubated human bile is studied by
biochemical analysis of precipitated crystals, polarizing quantitative light
microscopy and turbidimetric methods.
The present review
will focus on the recent advances in the field of pathobiology of cholesterol
gallstones, by underscoring the role of early events like water transport,
lipid transport, crystallization phenomena – including a genetic background -
in gallstone pathogenesis. Agents delaying or preventing precipitation of
cholesterol crystals and gallstone formation in bile will also be discussed.
[Back to top] WISH Cells as a Model for the “In Vitro”
Study of Amnion Pathophysiology
B.
Pavan,
In the course of pregnancy
amnion cells produce a number of factors which include cytokines and
prostaglandins (PGs) produced in response to autocrine, paracrine and endocrine
signals. Recent studies performed by several researchers contributed to
elucidate the mechanism through which amnion tissue is involved in the
triggering of physiological labor. However, there are other possible functions
to be ascribed to amniotic cells, depending on the high number of factors that
they produce as well as on the receptors that enable them to act in turn as
target. For instance, it has been demonstrated that amnion cells are able to
produce lecithin upon the regulation of several factors, such as
glucocorticoids and epidermal growth factor, a finding that suggests a
protective role of the tissue on fetal pulmonary function.
As regards to
triggering the uterine contractions, it is accepted that prostaglandin release
by amnion cells represents a key event. It is under the control of hormones,
growth factors, cytokines and probably PGs themselves. A striking analogy has
been found between the mechanism of inflammation and the onset of myometrial
activity in labor. In this context, it has been shown that for-Met-Leu-Phe
(fMLP), the prototype of a series of formylated peptides traditionally
considered chemotactic agents, is also involved in the regulation of amniotic
PG release. The similitude between labor and inflammatory response is enforced
by the antiprostaglandin action of some classes of antibiotics observed in
amnion tissue, that enable them as effective tools against preterm labor, both
in the absence and in the presence of infection.
As for the mechanisms
responsible for the regulation of PG synthesis, some agents act by influencing
protein synthesis, while others exert their effects through the production of
intracellular second messengers, mainly represented by
phosphatidyl-inositol-4-5 bisphosphate and cyclic AMP. The mechanism whereby
second messengers induce PG release is not clear, and a crosstalk between the
two transduction pathways could be hypothesized. This interaction has
extensively been analysed in “WISH” cells, a human amnion-derived cell line,
which represent a model for the in vitro study of amnion functions.
In the present review,
we intend to report the results of the studies regarding the mechanisms through
which the control of the above mentioned functions is executed.