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DURING THE PAST TWO DECADES the field of immunology has
witnessed a technical and scientific revolution that was accompanied by
a parallel explosion in related literature. Ground-breaking studies
have heralded a new day in understanding the potential role of various
proteins, including cytokines, chemokines, growth factors, and
receptors. This has been particularly relevant to research in bronchial
asthma. The prevalence of this heterogeneous and serious condition is
lamentably on the increase in both children and adults (5). Research
efforts by various laboratories around the world are accelerating and
increasing our understanding of the mechanisms regulating the
inflammatory response with a view to better therapy. It is now
generally recognized that inflammation may be responsible for the
damage to the airways. Eosinophils, regulated by various cytokines
including interleukin-5, interleukin-3, and
granulocyte/macrophage-colony-stimulating factor, appear
to be key effector cells in this condition (10). In pursuit of this, a
number of viable animal models of airway hyperresponsiveness and
allergic inflammation have been established and tested. Despite the
tremendous breakthroughs in understanding immunological processes in
general and inflammation in particular, asthma remains a mystery, an
unresolved jigsaw puzzle. Scientists are stymied by their relative inability to provide conclusive, as opposed to circumstantial, evidence
that ascribes precise roles for each component of the inflammatory
response associated with it.
The events leading to leukocyte migration from sites of hematopoiesis
to blood and ultimately to tissue are central in maintaining the
integrity of the immune system as well as in regulating inflammation (5, 10). In asthma, for instance, the selective recruitment of
eosinophils and memory T cells to the site of allergic reaction is a
prominent feature (1). Adhesion molecules are key in the influx and
recruitment of immune and inflammatory cells to the site of reaction
and their ultimate effector function. The discovery of these molecules,
their characterization, and the gradual elucidation of their potential
role are seen as turning points in our understanding of inflammation
(7).
The adhesion molecules involved in this process include integrins,
immunoglobulin-like molecules, and selectins (7). It is thought that
selectins, a family of three carbohydrate-rich adhesion receptors, are
involved in regulating the initial attachment and rolling of leukocytes
in capillaries, leading to their margination (6). Three different types
of selectin molecules have been described: P-selectin, E-selectin, and
L-selectin (platelet, endothelium, and leukocyte, respectively) (6). A
number of chemoattractant molecules have been implicated in initiating
leukocyte activation, leading to their firm anchoring on the
endothelium (1, 7). Members of the immunoglobulin family of adhesion
receptors (including integrins) are thought to play a role in
subsequent migration (diapedesis and extravasation) of these cells and
in interaction with various extracellular matrix proteins. The precise
role(s) played by each of these adhesion molecules is currently the
subject of intensive studies.
The collaborative study by an internationally respected team of
researchers in this field (2), represents a major contribution to our
current understanding of the role of P-selectin in airway inflammation.
The study was conducted in a P-selectin-deficient mouse model of
allergen (ovalbumin) -specific sensitization and challenge. De Sanctis
et al. (2) found that ovalbumin-sensitized and -challenged
P-selectin-deficient mice exhibited significantly reduced airway
eosinophilia and lymphocyte infiltration in bronchoalveolar lavage
fluid compared with similarly treated wild-type controls, whereas
immunoglobulin E response was unaffected. Airway hyperresponsiveness to
methacholine was also diminished in the knockout mice. These are
fascinating data that confirm studies that employed monoclonal antibody
treatment to downregulate P-selectin responses in vitro, ex vivo,
and in vivo (8, 9).
It is, however, important to take stock of these new observations and
see what can be learned from the use of transgenic mice, in which a
selective protein is overexpressed, and in mutant knockout mice, in
which expression for specific proteins is selectively deleted at the
molecular level. Both of these systems have provided important, but not
conclusive, answers to intractable questions about the role of specific
protein(s) in regulating immunological and inflammatory reactions (3,
4).
There are lessons for us from the data generated by the use of these
knockout and transgenic mouse models. The first is a confirmation that
phenotypes are ultimately the product of many ingredients, including,
among others, genetic expression and environmental factors. Second,
there is a high degree of redundancy within biological systems, which
has the potential to compensate for the loss of a particular
protein. We have witnessed that cells, their receptors, and mediators have a remarkable capacity, under certain circumstances, to switch paths and become involved in interactions beyond their identified roles. What is needed is a better understanding of the
intricate manner in which cells and their proteins communicate with
each other.
With the aid of new technologies, multidisciplinary research in such
fields as physiology, pathology, immunology, and cell and molecular
biology is turning up myriads of novel observations. The challenge is
to make sense of these data that are at once exciting and confusing.
The technique of differential display of mRNA is a case in point. It
opened new vistas for appreciating the potential inherent in the
genomic capacity of various biological systems. However, it also raised
more questions than it answered and led to its designation by some as
"differential dismay" technique. That being said,
biotechnological advances are critical if we are to unravel the secrets
of DNA protein synthesis and function.
Finally, a couple of points in regard to this and similar studies.
Although the data present clear a role for P-selectin in cell
recruitment and hyperresponsiveness in this model, we should exercise
caution while extrapolating from mice to humans. In addition, not all
the pieces of this jigsaw puzzle are in place yet. Many new molecules
are being discovered and characterized that are relevant to the complex
process of inflammation associated with asthma.
These studies continue to spur us on toward the goal of arriving at a
more sophisticated and safer treatment for asthma. In this quest, the
road is long and winding, and while there may be many signposts
pointing the way to our destination, only some of these will eventually
lead to "Rome"!
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