Research Interests:
A
recent large scale clinical study
demonstrated a 22% reduction in mortality of
patients on mechanical ventilation for Acute
Respiratory Distress Syndrome (ARDS) when
tidal volume was reduced from the
conventional 12 ml/kg to 6 ml/kg. This
clinical study was based on previous animal
experiments from our laboratory and others
showing that alveolar overdistention produces
microvascular injury and increased vascular
permeability. While previous hypotheses
have proposed a "stretched pore"
effect forcing open intracellular junctions
or a "stress failure" limited by
the tensile strength of the basement
membrane, recently studies from our
laboratory suggest that an active endothelial
cell response to mechanical stress
contributes significantly to the fluid and
protein leak observed at high vascular and
airway pressures. We have proposed that
calcium entry through non-selective stretch
activated cation channels (SACC) produces a
necessary increase in cell calcium that
triggers a permeability response utilizing
many of the signal pathways involved in
ligand mediated permeability increases. The
Ca++ /calmodulin/myosin light
chain kinase (MLCK) pathway has been
implicated by studies showing that increased
permeability in rat lungs due to lung
overdistention was blocked by inhibition of
either SACC, Ca++
/calmodulin, or MLCK. Calcium transients in
cultured pulmonary endothelial cells were
also prevented by inhibition of SACC or MLCK.
A possible role for tyrosine phosphorylation
involved in focal adhesions has been
suggested by isolated rat lung studies that
demonstrate an enhanced susceptibility to
mechanical injury after inhibition of protein
tyrosine phosphatase and a reduced injury
with inhibition of tyrosine kinase.
Separation of epithelium and endothelium from
basement membranes is a prominent feature of
ventilator induced lung injury (VILI) in
experimental animals suggesting a role of
cell adhesion in this injury. During the
tenure of a recently awarded 5 year
grant, we will explore the role of SACC using
cultured endothelial cells from each vascular
segment in the rat lung; artery, vein and
microcirculation, with new methods for
evaluating monolayer permeability under
strain and pressure. A state-of-the art
confocal microscope with multiple
fluorochrome capability will be used. In
addition, we have obtained the plasmid
containing the MID1 gene from yeast which
codes for the only SACC gene product cloned
to date. The responses of native and
transfected endothelial cells will be studied
using fluorescent analysis of intracellular
Ca++ and electrophysiologic
response using single channel patch clamp
methods. With these studies we hope to
characterize the events which initiate and
propagate increased vascular permeability
secondary to mechanical stress and identify
potential targets for pharmacological
intervention in patients.
An additional recent
direction in my laboratory has been the
development of a perfluorocarbon liquid
ventilator in cojunction with Mallard Medical
Co. of Redding, CA. This project is funded
through the SBIR/STTR program of NIH and
utilizes a patented method of liquid delivery
through a bias flow mode that improves both
gas exchange and fluid clearance from the
lung compared to conventional tidal liquid
ventilation. We are currently applying for
Phase II funding and will finalize prototype
designs for production. Controller algorithms
are being developed for optimal control of
tidal wave forms and automatic control of
residual liquid volumes in the lung for
efficient long term ventilation with minimal
peak alveolar pressures.
Recent Publications:
1. Parker, J.C., C. Ivey and J. Allan
Tucker. Gadolinium prevents high airway
pressure induced permeability increases in
isolated rat lungs. J. Appl. Physiol. 84(4):
1113-1118, 1998.
2. Parker, J.C., C. L. Ivey and J.A.
Tucker. Phosphotyrosine phosphatase
inhibition increases airway pressure induced
lung injury. J. Appl. Physiol. 85:1753-1761,
1998.
3. Parker, J.C., M.I. Townsley, and T.
Stevens. Ca2+ dependence of mechanical injury
in lung capillaries (letter). J. Appl.
Physiol. 86: 775-6, 1999.
4. Parker, J.C., and A. E. Taylor. Oxygen
toxicity. In: The lung at depth. Eds. C.E.G.
Lundgren and J.N. Miller. Vol 132: Lung
biology in health and disease. Series Ed. C.
Lenfant. Marcel Dekker, Inc. New York. Pages
165-210, 1999.
5. Parker, J.C., M.N. Gillespie, A.E.
Taylor, and S. L. Martin. Capillary
filtration coefficient, vascular resistance
and compliance in isolated mouse lungs. J.
Appl. Physiol. 87:1421-1427, 1999.
6. Parker, J.C.. Inhibitors of myosin
light chain kinase, phosphodiesterase and
calmodulin attenuate ventilator induced lung
injury. J. Appl. Physiol. In Press, 2000.
7. Parker, J.C., T. Stevens, and Sherri L.
Martin. Vascular segmental permeability after
high peak inflation pressure (PIP) injury in
isolated rat lungs. FASEB J. 14:A605, 2000.
8. Parker, J.C., and T. Stevens.
Mechanical stress induced calcium transients
in rat pulmonary artery and Microvascular
endothelial cells. FASEB J. 14:A693, 2000.
Mailing Address:
Department of Physiology
Room 3074 Medical Sciences Building
University of South Alabama
College of Medicine
Mobile, Alabama 36688
Phone: 251-460-6826
FAX: 251-460-6464
Click here for Dr. James C. Parker's
complete Curriculum
Vitae
