Research Interest
The primary focus of my research is centered on how neutrophils and
macrophages (of maternal or fetal origin) contribute to the initiation
and/or progression of embryonic and fetal toxicities after exposure
to selected environmental contaminants. These gestational toxicities
are potentially manifested as severe and irreversible developmental
abnormalities.
The adverse effects on fetal development after exposure to environmental
contaminants or biological pathogens are very important health concerns. In
many cases the mechanisms and targets of toxicity are well defined,
however, in others the parameters remain unclear. In the last
decade, it has become evident that the immune system can and does play
a significant role in the initiation and progression of toxicity induced
by chemicals or substances in adult subjects. Whether immune
cells of maternal origin play a role in the initiation and/or progression
of various developmental toxicities after exposure to specific agents
is unclear. There is very little published information addressing
the functional capabilities of fetal neutrophils and macrophages in
developmental toxicities. In addition, the potential mediators
and mechanisms by which these cells induce fetotoxicity require further
clarity. It is my goal to provide that clarity in these regards.
My secondary research interest is focused on understanding the mechanisms
propagating neutrophil-dependent hepatocellular toxicity after exposure
to selected hepatotoxicants and environmental contaminants.
For example, the acute hepatotoxicity induced by alpha-naphthylisothiocyanate
(ANIT) in rats is manifested as neutrophil-dependent necrosis of bile
duct epithelial cells (BDECs) and hepatic parenchymal cells. This
hepatotoxicity mirrors that of drug-induced cholangiolitic hepatitis
in humans. Since BDECs are primary targets of ANIT-induced toxicity,
we hypothesized that after exposure to ANIT, BDECs produce a factor(s)
that modulates neutrophil chemotaxis and neutrophil-dependent hepatocellular
injury. Through the use of centrifugal elutriation, gradient
separation techniques, cell culture systems, protein isolation techniques,
immunohistochemical and histological analysis, biochemical analysis,
and protein analysis, we were able to demonstrate in vitro that BDECs
in response to ANIT, produce chemokine-like factor(s) that chemoattracts
neutrophils and stimulates them to release the cytolytic proteases,
cathepsin G and elastase. After their release, these proteases
cause hepatocellular injury that is manifested as necrosis of the hepatic
parenchyma and release of essential biochemical enzymes. We also
demonstrated that the administration of specific antiproteases to our
culture system affords complete protection against the observed toxicities. Our
future studies will be designed to further identify/characterize the
BDEC-derived factor(s) that regulate neutrophil activity, to further
characterize the hepatocellular toxicity induced by neutrophil-derived
proteases and apply the information acquired from our in vitro studies
to an in vivo model system.
The purpose of this research is to understand the mechanisms involved
in neutrophil-dependent hepatocellular pathologies (e.g. cholestasis)
so that more effective prophylactic therapies can be developed. |
