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Campus Address
920-N CSB
840 South Wood Street (MC 719)
Chicago, Illinois 60612-7323
jwc@uic.edu
Clinical and Research Interests
Dr. Christman is interested in general critical care medicine
with special interests in
management of patients with severe sepsis and the acute respiratory
distress
syndrome (ARDS). In addition, Dr. Christman attends a weekly
general pulmonary
clinic at the Jesse Brown VAMC, where he provide special expertise
in the management
of chronic obstructive pulmonary disease (COPD) and occupational
mineral dust lung
diseases (asbestosis and silicosis).
Dr. Christman's laboratory program investigates the role of
transcription factors in
macrophage gene expression in the context of cellular and animal
models of lung
inflammation. The members of Dr. Christman's laboratory are
Gye Young Park, MD,
Anser Azim PhD, Xuerong Wang MD, Biji Mathews PhD, and Hongmei
Cai. The laboratory
is funded by both the National Instututes of Health and the
Department of Veterans
Affairs as described below.
Key Words: Toll-like receptor 4, PU.1, NADPH oxidase, nuclear
factor ?B, reactive
oxygen species, chemokine, macrophage, neutrophil, lung, endotoxin,
inflammation,
transgenic, knock-out, ARDS, SIRS, MODS.
Current Research Projects
NIH R01 HL 075557-01 (Principal Investigator - J. Christman,
2003-2007).
This grant,"Macrophage Gene Expression in Acute Lung Injury",
is designed to
investigate the basic molecular mechanism by which the ets-family
transcription
factor, PU.1 is involved in the response of macrophages to endotoxin
with the hope
that this leads to novel treatments for ARDS.
Abstract:
The mechanisms that regulate inflammatory response in humans
with severe sepsis
need to be better defined in order to design specific therapies
that can be used to
protect the lungs and prevent death from multiple organ failure.
Pulmonary macrophages
are immune-effector cells that mediate the molecular pathobiology
of neutrophilic lung
inflammation in response to endotoxin. The overall goal of this
proposal is to investigate
whether PU.1 gene expression is critical determinant of pulmonary
macrophage
involvement in ARDS. We hypothesize that PU.1 regulates the
response of pulmonary
macrophages to endotoxin through two integrated mechanisms:
a) induction of Toll-like
receptors that can trigger the NF-kB activation pathway and
b) through enhancement
of inflammatory gene production, such as COX-2, that contributes
to the development
of cytokine and chemokine mediated lung inflammation. We propose
three specific aims:
1) To define changes in PU.1 gene expression or activation state
in response to
treatment with endotoxin, 2) To determine the mechanisms by
which PU.1 increases
production of inflammatory mediators in response to treatment
with endotoxin, and 3)
To identify the relative contribution of PU.1 to the development
of neutrophilic lung
inflammation in a murine model of peritoneal sepsis. In the
setting of severe sepsis,
signaled recruitment of differentiation of macrophages may represent
a renewable pool
of endotoxin responsive pulmonary macrophages that contribute
to the initiation,
intensity, and duration of neutrophilic lung inflammation. Our
studies are designed to
investigate the basic molecular mechanism by which PU.1 is involved
in the response of
macrophages to endotoxin with the hope that this leads to novel
treatments for ARDS.
Department of Veterans Affairs Merit Review Grant (Principal
Investigator - J. Christman, 2004-2009). This grant is in
its 15-20 year and is entitled "Regulation of Neutrophilic
Inflammation" and addressed the interaction between NADPH
oxidase, toll-like 4 receptors, PU.1 and nuclear factor kappa
B in the pathogenesis of neutrophilic lung infalmmation.
Abstract:
The acute respiratory distress syndrome (ARDS) associated with
Gram-negative sepsis has a substantial morbidity and high mortality.
Accumulating clinical data indicate that macrophages have a
central role in the pathogenesis of neutrophilic lung inflammation
that leads to ARDS but specific molecular pathways in macrophages
have not been defined. We have reasoned that detailed knowledge
of regulatory pathways in macrophages could lead to new treatments
for ARDS. Our overall goal is to define interactions among critical
regulatory pathways in macrophages that contribute to the initiation
and progression of neutrophilic lung inflammation. Four integrated
hypotheses will be addressed in the context of endotoxin-induced
neutrophilic lung inflammation. 1) toll-like receptor 4 (TLR4)
and accessory proteins on macrophages are essential for generation
of neutrophilic lung inflammation, 2) reactive oxygen species
via the membrane bound NADPH oxidase enzyme complex regulates
macrophage activation by modulating activation of the NF-?B
pathway in response to endotoxin, 3) activation of NF-?B in
macrophages is fundamentally necessary for generation of neutrophilic
lung inflammation, and 4) PU.1 is a co-regulatory partner, along
with NF-?B that augments macrophage production of key inflammatory
proteins that contribute to the initiation and progression of
neutrophilic lung inflammation. These hypotheses will be addresses
with two specific aims: SA 1: To determine the necessity of
macrophage toll-like 4 receptors and NADPH oxidase for the development
of neutrophilic lung inflammation in response to treatment with
endotoxin. Our approach will be to use fetal liver transplantation
(FLT) to reconstitute TLR4 and NADPH deficient macrophages in
wild-type mice in order to examine the impact of macrophage
TLR4 and NADPH oxidase on the response to endotoxin in mice.
Recently, TLR4 receptors and components of NADPH oxidase system
have been identified in cells other than macrophages, including
endothelial cells but the relative contribution of these protein
complexes in individual cell types to lung inflammation is not
clear. We will address the importance of macrophage TLR4 gene
expression and NADPH oxidase by generating reciprocal bone marrow
chimerics with TLR4-/- null donor and wild-type recipient mice
and NADPH oxidase (p47phox) -/- null donor and wild-type recipient
mice, respectively. The relative importance of macrophage TLR4
and NADPH oxidase will be identified by determining the magnitude
of differences in the endotoxin response between these knockout
and wild-type bone marrow chimeric mice. We think that isolating
the relative role of macrophage TLR4 and NADPH oxidase to macrophage
will lead to cell directed interventions in the pathogenesis
of ARDS. SA-2: To determine whether PU.1 contributes to the
endotoxin response by regulating macrophage phenotype and acting
as a co-regulatory partner with NF-?B to augments production
of pro-inflammatory mediators. We have observed that PU.1 regulates
TLR4 and COX-2 gene expression and therefore influences the
sensitivity of macrophages to endotoxin and could modulate the
inflammatory response, respectively. We propose to address the
critical role of PU.1 to the endotoxin response by using a duel
approach. First, we will employ a chromatin immunoprecipitation
(ChIP) assay to determine the timing and intensity of binding
of PU.1 to the promoters of inflammatory genes (including TLR-4
and COX-2) in lung macrophages from endotoxin-treated mice.
This approach has the unique advantage of detecting PU.1 interactions
with endogenous TLR4 and COX-2 genes in the context of whole
animal model of ARDS. For these studies, we will use a ChIP
assay on whole lung tissue and lung macrophages from endotoxin-treated
mice. Second, we will examine the evolution of the endotoxin
response in conditional PU.1 knock-in mice. Macrophages from
these mice lack PU.1 but normal PU.1 levels can restored by
treating the mice with Tamoxifan, allowing us to identify the
full impact of PU.1 on inflammatory gene expression. These studies,
together, should provide important and unique insights into
the molecular regulation of neutrophilic lung inflammation,
and could provide evidence for novel therapeutic approaches
to limit lung injury and restore health in patients suffering
from ARDS and other inflammation diseases.
Recent
Publications
(among over 90 peer-reviewed, published and submitted manuscripts):
Sadikot
RT, Yull FE, Zeng H, Kernodle DR, Janson ED, Contag CH, Holland
SM, Blackwell TS, Christman JW. P47phox deficiency impairs
NF-?B activation and host defense in Pseudomonas pneumonia.
J Immunology 2004 Feb 1;172(3):1801-8.
Maus
UA, Srivastava M, Paton JW, Mack M, Everhart MB, Blackwell TS,
Christman, JW, Schlöndorff D, Seeger W, Lohmeyer J.
Pneumolysin induced lung injury is independent of leukocyte
trafficking into the alveolar space. J Immunol. 2004 Jul 15;173(2):1307-12
Sadikot
RT, Christman JW, Blackwell TS. Molecular Targets for
Modulating Lung Inflammation and Injury. Curr Drug Targets.
2004 Aug;5(6):581-8
Maus
UA, Wellmann S, Hampi C, Kuziel WA, Srivastava M, Mack M, Everhart
MB, Blackwell TS, Christman JW, Schlondorff D, Bohle RM, Seeger
W, Lohmeyer J.CCR2 positive monocytes recruited to inflammed
lungs downregulate local CCL2 chemokine levels: Description
of a novel negative feedback loop. Am J Physiol Lung Cell Mol
Physiol. Feb;288(2):L350-8. Epub 2004 Oct 29.2005
Everhart,
M.B., Han, W., Parman, K.S., Polosukhin, V.V., Li, B., Yull,
F.E., Christman, J.W., Blackwell, T.S. Intratracheal
administration of liposomal clodronate accelerates alveolar
macrophage reconstitution following fetal liver transplantation.
J Leukoc Biol. Feb;77(2):173-80. Epub 2004 Nov 24.2005
Joo
M, Hahn YS, Sadikot RT, Blackwell TS, and Christman JW.
Hepatitis C Virus Core Protein Suppresses NF-kB Activation by
Direct Interaction with IKK? Journal of Virology Jun;79(12):7648-57.2005
Sadikot
RT, Blackwell TS, Christman JW, Prince AS. Pathogen-Host
Interactions in Pseudomonas aeruginosa Pneumonia: The State
of the Art. Am J Resp and Crit Care Med, 171, 1209-1223, 2005
Pedchenko
TV, Park GY, Joo M, Blackwell TS, Christman JW. Inducible
Binding of PU.1 and interacting Proteins to the Toll-Like Receptor
4 Promoter During Endotoxemia. In press, American Journal of
Physiology, Lung Cell and Molecular Biology 2005
Park
GY, Christman JW. Nuclear factor kappa B is a promising
therapeutic target in inflammatory lung disease In press Current
Drug Target 2005
Sadikot
RT, Zeng H, Joo M, Yull FE, Cheng DS, Christman JW, Blackwell
TS. RelA over-expression in airway epithelium enhances
bacterial clearance and host defense in P. aeruginois pneumonia
in J of Immunology 2005 in press
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