| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
(PPAR-) activation suppresses ischemic induction of Egr-1 and its inflammatory gene targets
College of Physicians & Surgeons of Columbia University, New York, New York, USA
1Correspondence: Columbia University, College of Physicians and Surgeons, PH 10 Stem, 630 West 168th St., New York, NY 10032, USA. E-mail: djp5{at}columbia.edu
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
inhibits induction of Egr-1. Egr-1 is rapidly induced in murine lungs after ischemia-reperfusion, as well as in alveolar mononuclear phagocytes deprived of oxygen as an ischemic model. In vitro, the natural PPAR- ligand (15-deoxy-
12,14-prostaglandin J2) and a PPAR- activator (troglitazone), but not a PPAR-
activator (bezafibrate), strikingly diminished Egr-1 mRNA and protein expression and nuclear DNA binding activity corresponding to Egr-1. In vivo, treatment with troglitazone before ischemia prevented induction of Egr-1 and its target genes such as interleukin-1ß, monocyte chemotactic protein-1, and macrophage inflammatory protein-2. As a consequence of PPAR- activation, pulmonary leukostasis was decreased and oxygenation and overall survival were improved. Activation of PPAR- suppresses activation of Egr-1 and its inflammatory gene targets and provides potent protection against ischemic pulmonary injury. These data reveal a new mechanism whereby PPAR- activation may decrease tissue inflammation in response to an ischemic insult.—Okada, M., Yan, S. F., Pinsky, D. J. Peroxisome proliferator-activated receptor- (PPAR-) activation suppresses induction of Egr-1 and its inflammatory gene targets in ischemic lungs.
Key Words: ischemia • reperfusion • early growth response-1 • troglitazone
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
2
3
4)
. Hypoxia or tissue ischemia triggers rapid induction of Egr-1 mRNA, protein, and nuclear binding activity in an HIF-1-independent manner (5)
. More recently, we have demonstrated that the induction of Egr-1 under conditions of ischemic vascular stress is a vital common denominator underlying induction of many different genes that encode diverse activators of inflammation and coagulation. Egr-1 induction therefore sets the stage for subsequent tissue injury during reperfusion (1
, 6)
.
The peroxisome proliferator-activated receptor (PPAR-) has come under recent scrutiny as a potentially important transcription factor that modulates the inflammatory response of monocytes, which may underlie some of the anti-inflammatory effects of salicylates in rheumatoid arthritis (7)
. PPAR- ligands were shown to inhibit the production of nitric oxide and macrophage-derived cytokines, i.e., tumor necrosis factor, interleukin-1 (IL-1), and IL-6 at least in part by antagonizing the activation of transcription factors such as nuclear factor-kappaB (NF-
B) (7
, 8)
. PPAR-, a member of the nuclear hormone receptor superfamily, was originally reported to be highly expressed in adipocytes and to play a critical role in their differentiation (9
, 10)
. It is activated by the natural ligand 15-deoxy-12,14-prostaglandin J2 (15D-PGJ2) (11)
as well as the synthetic ligand thiazolidinedione (12)
. Because the PPAR- gene is expressed in mononuclear phagocytes (7)
, which respond to hypoxia or ischemia with an exuberant Egr-1-dependent inflammatory response (1
, 5)
, we hypothesized that, physiologically, PPAR- expression may serve as an endogenous mechanism to dampen this pathological response to ischemia triggered by Egr-1 induction. Experiments were undertaken to determine whether endogenous PPAR- modulates induction of Egr-1 and its inflammatory gene targets in response to ischemic or hypoxic stress.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
ligands were obtained from the following sources: troglitazone was provided by Sankyo Pharmaceutical Co. (Tokyo, Japan); 15-D-PGJ2 was purchased from Cayman Chemical Co. (Ann Arbor, MI). The PPAR- ligand bezafibrate was obtained from Sigma Chemical Co. (St. Louis. MO). These PPAR ligands were dissolved in minute quantities of DMSO (final concentration 0.005%). PPAR ligands were added 6 h before induction of hypoxia. Using an environmental chamber described previously (5)
, cells were subjected to 30 min hypoxia (pO2 in the medium 
12–14 torr). This time was chosen because we had shown it to be the time of maximal Egr-1 expression in hypoxic macrophages. Cells subjected to hypoxia were placed in medium preequilibrated with the hypoxic gas mixture just before placement in the environmental chamber. Thus, cultures were immersed immediately in the oxygen-deprived environment at the time of medium change, coinciding with time of placement in the chamber.
Murine ischemia/reperfusion model
C57BL6/J mice (male, 12–15 wk old) purchased from Jackson Laboratories (Bar Harbor, ME) were used in these experiments according to a protocol approved by the Institutional Animal Care and Use Committee at Columbia University, in accordance with guidelines of the American Association for the Accreditation of Laboratory Animal Care.
Troglitazone was administered to mice by oral gavage (0.1 mL/mouse) for 7 days at doses of 0, 5, and 100 mg/kg/day, prepared as a suspension in 0.5% methylcellulose solution. For control experiments, methylcellulose solution alone was used for gavage (these experiments are referred to as "vehicle" controls). The ischemia/reperfusion stress followed on day 8. Animals were initially anesthetized intraperitoneally (i.p.) with 0.1 mg/g mouse weight (ketamine) and 0.01 mg/g mouse weight (xylazine), followed by i.p. infusion of one third of the initial dose per hour controlled. After ensuring appropriate depth of anesthesia, mice were intubated via tracheotomy and placed on a Harvard ventilator (tidal volume=0.5 mL, respiratory rate=120/min) with room air, followed by bilateral thoracotomy. The left hilum was cross-clamped for 1 h, followed by 30 min to 3 h reperfusion (exact times are identified in Results and figure legends). Lung specimens were excised just after reperfusion for Northern or Western blot analysis. Survival was measured 1 h after circulatory exclusion of the nonoperated lung (by ligating the right hilum), which was performed after both the ischemic and reperfusion (3 h) periods had elapsed. In a separate series of experiments, lung function was ascertained by arterial blood gas analysis in mice that survived for 5 min after right hilar ligation.
Northern blot
Total RNA (20 µg/lane) obtained from cultured mononuclear phagocytes or murine lung tissue after homogenization was extracted using Trizol (Life Technologies, Rockville, MD) and subjected to electrophoresis in 0.8% agarose-formaldehyde gels, followed by capillary transfer to Duralon-UV membranes (Stratagene, La Jolla, CA). Membranes hybridized with 32P-labeled cDNA probes for Egr-1, IL-1ß, monocyte chemoattractant protein-1 (MCP-1), or macrophage inflammatory protein-2 (MIP-2) (1)
were subsequently exposed to Kodak Biomax film at -80°C. Membranes were then stripped and rehybridized with radiolabeled ß-actin cDNA as a control for RNA loading and transfer efficiency.
Western blot
Extracts of cultured mononuclear phagocytes or murine lung tissue homogenate were mixed with a protease inhibitor mixture (Roche Molecular Biochemicals, Mannheim, Germany) and 20 µg of protein was loaded into each lane of a SDS-polyacrylamide gel (7.5%). After application of appropriate voltage across the gel to separate proteins according to size, proteins were transferred electrophoretically to nitrocellulose membranes. Immunoblotting was performed using a primary rabbit anti-mouse Egr-1 IgG (Santa Cruz Biotechnology, Santa Cruz, CA) and a rabbit anti-mouse Sp-1 IgG (Santa Cruz Biotechnology). Secondary detection of sites of primary antibody deposition was accomplished using a horseradish peroxidase-conjugated goat anti-rabbit IgG (Sigma Chemical Co). Final detection of immunoreactive bands was done with the enhanced chemiluminescent Western blot system (Amersham International, Buckinghamshire, England).
Electrophoretic mobility gel shift assay
The assay was performed on nuclear extracts from cultured mononuclear phagocytes by the method of Dignam et al. (13)
. Probes for Egr (Santa Cruz Biotechnology) were 5' end-labeled with [32P]ATP (3000 Ci/mmol) using T4 polynucleotide kinase. Binding reactions were done as described (14)
; samples were loaded directly onto nondenaturing polyacrylamide/bisacrylamide (4%) gels (10 µg of protein in each lane). Competition experiments were performed by adding a 100-fold molar excess of unlabeled Egr probe. Supershift experiments were done by preincubating samples with anti-mouse Egr-1 antibody (Santa Cruz Biotechnology) for 1 h at 4°C before application to the gel. Electrophoresis was performed at room temperature for 2 h at 200 V.
Immunofluorescence
Lung tissue was harvested, washed, embedded, frozen, and sectioned into 5 µm sections with a cryostat. The sections were fixed in acetone and incubated with a rabbit polyclonal anti-rat Egr-1 antibody (1:100 dilution; Santa Cruz) and rhodamine-conjugated donkey anti-rabbit IgG (1:50 dilution; Santa Cruz). Sections were then incubated with fluorescein isothiocyanate (FITC) -conjugated rat anti-mouse macrophage antibody (F4/80; 1:20 dilution; Caltag Laboratories, Burlingame, CA). For confocal microscopy, antigen detection was accomplished using a Zeiss LSM410 laser scanning confocal microscope with epifluorescent illumination (excitation wavelength 568 nm for rhodamine, 488 nm for FITC).
Myeloperoxidase assay
Tissue myeloperoxidase activity was measured as an index of graft leukocyte accumulation. This assay was performed as described (15)
and data are expressed as change in absorbance at 460 nm per minute.
Statistics
All statistical comparisons were done using commercially available statistical software (STAT VIEW-J 5.0, Abacus Concepts) on Macintosh G4 PowerPC computer. One-way ANOVA was used to make statistical comparisons among different conditions. Survival was estimated by the Kaplan-Meier method, with differences in survival determined by log-rank analysis. Values are expressed as mean ± SE, with differences considered statistically significant when P < 0.05.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
activators on Egr-1 expression in hypoxic mononuclear phagocytes activators could inhibit the increased expression of Egr-1 observed in hypoxic mononuclear phagocytes. Egr-1 mRNA levels measured 30 min after exposure to hypoxia were markedly elevated in the group of cells treated with DMSO alone as a control (Fig. 1
A, second lane). A similar degree of Egr-1 mRNA induction was noted in the group of cells treated with the PPAR- activator bezafibrate. However, when cells were treated with 15-D-PGJ2 or troglitazone but otherwise subjected to identical hypoxic procedures, Egr-1 mRNA levels were significantly reduced (Fig. 1A
, lanes 4, 5). Concordant with these observations, analyses of the expression of Egr-1 protein showed that 15-D-PGJ2 or troglitazone, but not bezafibrate, significantly inhibited increased levels of Egr-1 protein detected by Western blot after hypoxia (Fig. 1B
). The effect of PPAR- activators to reduce expression of Egr-1 was specific in that a related transcription factor (Sp-1) was not affected. To confirm that the measured decreases in Egr-1 mRNA and protein with PPAR- activators were associated with reduced Egr-1/DNA binding in nuclear extracts taken from alveolar macrophages, electrophoretic gel mobility shift assays were performed on nuclear extracts from NR8383 cells using a 32P-labeled consensus oligonucleotide probe for Egr. These experiments demonstrated that although there was no discrete gel shift band in nuclear extracts of untreated nonhypoxic cells (Fig. 1C
, lane 2), a dense band was observed in nuclear extracts of both DMSO-treated (Fig. 1C
, lane 3) and bezafibrate-treated (Fig. 1C
, lane 7) cells obtained 30 min after exposure to hypoxia. In sharp contrast, pretreatment of cells with the PPAR- ligands 15-D-PGJ2 or troglitazone virtually abrogated the gel retardation band associated with Egr-1/DNA binding (Fig. 1C
, lanes 4–6). Supershift experiments were also performed to confirm the authenticity of the DNA binding species responsible for retardation of electrophoretic mobility in the gel as Egr-1. An anti-mouse Egr-1 antibody added to the reaction mixture caused a supershift (Fig. 1C
, lane 8), indicating that the gel shift band represented DNA interaction with authentic Egr-1. Further evidence for the Egr specificity of the protein-DNA interaction was shown by competition experiments in which a 100-fold molar excess of unlabeled Egr probe obliterated the appearance of the gel shift band (Fig. 1C
, lane 9).
|
Induction of Egr-1 in murine lungs exposed to ischemia and reperfusion
The time course of Egr-1 expression after lung ischemia was initially examined by Northern blot analysis. Clamping of the pulmonary hilum for 1 h caused a detectable increase in the density of the band corresponding to Egr-1 mRNA, with a more pronounced increase in Egr-1 mRNA levels detected after reperfusion. Egr-1 mRNA levels peaked 30 min after reperfusion and subsequently tapered off based on densitometric analysis of multiple blots (Fig. 2
A). A rapid increase in Egr-1 protein was observed along nearly the same time course with a minor rightward temporal shift, as could be expected based on the time required to translate nascent mRNA. Peak expression of Egr-1 protein was observed 1 h after reperfusion (Fig. 2B
). Expression of Egr-1 protein relative to the expression of an unrelated zinc finger family transcription factor (Sp-1) was increased based on densitometric analysis of multiple blots.
|
To ascertain sites of Egr-1 expression after reperfusion, immunohistochemical analysis was performed on lung tissue. Fluorescent immunohistochemistry of untreated naïve lungs indicated that Egr-1 antigen was virtually undetectable (Fig. 2C
). When sections from lung tissue that had been cross-clamped at the hilum for 1 h, then reperfused for 1 h, were subjected to the same immunostaining procedures, Egr-1 immunoreactivity was shown to be significantly increased in the medial smooth muscle as well as mononuclear phagocytes (identified by the colocalization of the fluorescence signals of rhodamine-conjugated anti-Egr-1 and FITC-conjugated F4/80) (Fig. 2D
).
Effects of troglitazone on Egr-1 expression in ischemic/reperfused murine lungs
The next experiments tested whether a PPAR- agonist such as troglitazone could reduce the increased expression of Egr-1 observed in reperfused lungs. Egr-1 mRNA levels measured 1 h after reperfusion were markedly elevated in the group of lungs from mice given vehicle alone (Fig. 3
A). However, when mice were treated with troglitazone but otherwise subjected to identical ischemia/reperfusion procedures, Egr-1 mRNA levels were significantly decreased in a dose-dependent manner. Concordant with these observations, analyses of the expression of Egr-1 protein showed that troglitazone significantly inhibited increased levels of Egr-1 protein observed after ischemia/reperfusion (Fig. 3B
). The effect of troglitazone to reduce Egr-1 expression was specific in that a related transcription factor (Sp-1) was not affected.
|
Effects of troglitazone on lung function and leukocyte accumulation
To ascertain the functional effects of PPAR- activation in ischemia/reperfusion-injured lungs, gas exchange was measured after having treated mice with vehicle alone or with troglitazone. Because a critical hallmark of lung injury in the setting of ischemia/reperfusion is impaired gas exchange, arterial oxygenation (PaO2) was measured after circulatory exclusion of the nonischemic (right) lung. Arterial oxygenation remained excellent after circulatory exclusion of the right lung in untreated animals whose left lungs were not subjected to ischemia/reperfusion (leftmost bar, Fig. 4
A). Although arterial oxygenation markedly deteriorated in mice whose left lungs were subjected to ischemia/reperfusion in the absence of troglitazone pretreatment, arterial oxygenation was significantly increased in mice pretreated with troglitazone. To investigate whether inflammatory tissue injury was also affected by PPAR- activation, myeloperoxidase activity in lungs was measured as an index of leukocyte accumulation. Troglitazone significantly reduced the elevated levels of myeloperoxidase activity observed after ischemia/reperfusion (Fig. 4B
).
|
Effects of troglitazone on cytokine/chemokine expression
A major facet of the clinical response to tissue ischemia/reperfusion injury results from amplification of the inflammatory response. To investigate the contribution of proinflammatory cytokines to postischemia/reperfusion lung injury, expression of several prototypical Egr-1 inflammatory target genes was examined. IL-1ß mRNA expression was strongly up-regulated in lungs exposed to ischemia/reperfusion; this up-regulation was significantly suppressed by administration of troglitazone, but not vehicle (Fig. 4C
). Because of the prominent role for recruited leukocytes in lung ischemia/reperfusion injury, expression of the Egr-1 target genes MCP-1 and MIP-2 was examined. MCP-1 and MIP-2 are CC and CXC chemokines that predominantly direct monocytes and neutrophils (respectively) to sites of inflammation (16
, 17)
. Lungs subjected to ischemia/reperfusion showed elevated mRNA levels of MCP-1 and MIP-2 transcripts (Fig. 4D, E
), but these increases were significantly suppressed by the PPAR- agonist troglitazone.
Effects of troglitazone on murine survival after lung ischemia/reperfusion injury
Survival of mice exposed to ischemia/reperfusion depends on the convergence of a multitude of competing effector mechanisms. Therefore, the effect of troglitazone on murine survival was tested in a stringent model, in essence to summate all effector mechanisms that may be actuated or suppressed in vivo. Although survival was extremely poor after ischemia of 1 h and reperfusion of 3 h, at the predefined end point of 1 h following circulatory exclusion of the nonischemic lung in vehicle-treated mice (10% survival), troglitazone-treated mice fared four times better (40% survival, Fig. 4
F). These data demonstrate that pretreatment with the PPAR- agonist troglitazone, which not only suppresses Egr-1 gene expression but also reduces expression of Egr-1 target genes, confers both functional and survival advantages in the setting of lung ischemia/reperfusion injury.
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
, 5)
. The consequence of this activation is the induced expression of the protein products of divergent families of genes, which are teleologically related in that they all modulate the tissue response to injury. Egr-1 mRNA, protein, and activity are barely detectable under baseline conditions, but there is a rapid and pronounced expression of each after lung ischemia/reperfusion or hypoxia in murine models (1)
. Because many different genes possess Egr-1 response elements in their promoter regions, there are many different gene families whose induction is triggered by ischemic stress through the activation of Egr-1. These include procoagulant genes such as tissue factor and plasminogen activator inhibitor-1, as well as inflammatory genes such as intercellular adhesion molecule-1, IL-1ß, and chemokines (1)
. There is ample evidence to suggest that cytokine expression goes up markedly after bouts of ischemia and reperfusion (18
, 19)
and that this cytokine expression is causally related to deleterious clinical consequences. Recent work demonstrates that in a lung transplant model, a strategy of Egr-1 suppression can prevent ischemia/reperfusion-induced inflammation and protect the vulnerable lungs by dampening the production of cytotoxic and proinflammatory cytokines (6)
. However, the antisense Egr-1 oligodeoxynucleotide approach used in the lung transplant model is not likely to be applicable to some clinical settings in which similar Egr-1-triggered mechanisms of tissue injury apply. Therefore, the current studies are important because they highlight a potential link between two endogenous transcriptional pathways (PPAR- and Egr-1) that may interact directly in ischemic tissue to modulate expression of genes responsible for tissue injury. Because PPAR- agonists are currently in widespread clinical use, albeit for different conditions (insulin sensitization in diabetics), the current studies are provocative in that they suggest other important endogenous pathways that may be modulated by PPAR- agonists for which there are currently no approved therapeutic modalities.
The most meaningful finding of the present study is that treatment with troglitazone significantly inhibits ischemia-driven activation of Egr-1 both in vitro and in vivo, which suggests a new transcriptional mechanism by which PPAR- agonists may protect against inflammation. Stimulating the PPAR- pathway resulted in a significant improvement in lung function and survival, a decrease in mRNA levels of IL-1ß, MIP-2, and MCP-1 expression, as well as a reduction in leukostasis in murine model of lung ischemia/reperfusion-induced injury. Because these genes are downstream targets of Egr-1 (1)
, this suggests a functional link between PPAR--mediated inhibition of Egr-1 activation in ischemic lung tissue. Because chemokine-mediated leukocyte recruitment has a pivotal role in controlling the inflammatory reaction to ischemic injury (20)
, the reduction of which is recognized to enhance postischemic organ function, these data suggest a potential cascade by which PPAR- activation can lead to protection against ischemia/reperfusion-related injury.
The current studies add to the growing recognition of the importance of PPAR- in the vasculature. Activation of PPAR- has been shown to inhibit vascular cell adhesion molecule expression in endothelial cells, leading to inflammatory actions of macrophages implicated in vascular injury (7)
. Endogenous PPAR- has also recently been shown to protect against intestinal ischemia/reperfusion injury (21)
, with a suggested mechanism requiring suppression of the transcription factor NF-B. Other investigators have suggested a role for PPAR- as a negative modulator of the expression of proinflammatory genes through antagonism of the activities of other transcription factors such as activator protein-1, signal transducers, and activators of transcription-1 (8
, 22
, 23)
. Although the current data do not refute the possibility that PPAR- agonism may elicit alternative transcriptional mechanisms of cytoprotection, to our knowledge these are the first data to directly implicate a link between PPAR- and Egr-1 in the setting of ischemia/reperfusion injury.
The current studies do not completely exclude the possibility that troglitazone inhibits Egr-1 expression through additional mechanisms that are independent of PPAR-. Troglitazone has a vitamin E moiety that could theoretically contribute to its anti-inflammatory activity through antioxidant effects (24)
. Whether the dose of vitamin E provided by troglitazone in the present study is enough to affect vascular injury is doubtful. At 100 mg/kg troglitazone per day, mice received the equivalent of 2 IU of vitamin E, a dose much lower than that reported to affect ischemia/reperfusion-driven injury (24
, 25)
. Other data demonstrate that another PPAR- ligand, ciglitazone, which does not contain the vitamin E moiety, also suppresses hypoxia-driven Egr-1 induction in macrophages (not shown). Additional evidence supporting the assumption that the suppressive effect of troglitazone on Egr-1 expression was not dependent on antioxidant effects is provided by our parallel study showing that the natural ligand 15-D-PGJ2, which has among its properties a direct binding affinity with PPAR-, inhibited hypoxia-induced expression of Egr-1 in macrophages with equal potency as troglitazone.
These data allow us to posit the existence of a biologically relevant link between two pathways of transcriptional activation, PPAR- and Egr-1, in the setting of ischemia and reperfusion injury. Although further testing is clearly required, given the potential for harm caused by Egr-1 induction in hypoxic or ischemic tissue, these data open the door to a potentially new therapeutic modality for Egr-1 suppression and tissue protection that may be relevant for disease such as myocardial infarction and stroke and conditions such as organ transplantation.
|
ACKNOWLEDGMENTS |
|---|
Received for publication May 29, 2002. Accepted for publication August 7, 2002.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  W.-Y. Zhang, E. A. Schwartz, P. A. Permana, and P. D. Reaven Pioglitazone Inhibits the Expression of Inflammatory Cytokines From Both Monocytes and Lymphocytes in Patients With Impaired Glucose Tolerance Arterioscler. Thromb. Vasc. Biol., December 1, 2008; 28(12): 2312 - 2318. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. D. Wiggin, M. Kretzler, S. Pennathur, K. A. Sullivan, F. C. Brosius, and E. L. Feldman Rosiglitazone Treatment Reduces Diabetic Neuropathy in Streptozotocin-Treated DBA/2J Mice Endocrinology, October 1, 2008; 149(10): 4928 - 4937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Bhattacharyya, S.-J. Chen, M. Wu, M. Warner-Blankenship, H. Ning, G. Lakos, Y. Mori, E. Chang, C. Nihijima, K. Takehara, et al. Smad-Independent Transforming Growth Factor-{beta} Regulation of Early Growth Response-1 and Sustained Expression in Fibrosis: Implications for Scleroderma Am. J. Pathol., October 1, 2008; 173(4): 1085 - 1099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hoetzel, T. Dolinay, S. Vallbracht, Y. Zhang, H. P. Kim, E. Ifedigbo, S. Alber, A. M. Kaynar, R. Schmidt, S. W. Ryter, et al. Carbon Monoxide Protects against Ventilator-induced Lung Injury via PPAR-{gamma} and Inhibition of Egr-1 Am. J. Respir. Crit. Care Med., June 1, 2008; 177(11): 1223 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Napimoga, S. M. Vieira, D. Dal-Secco, A. Freitas, F. O. Souto, F. L. Mestriner, J. C. Alves-Filho, R. Grespan, T. Kawai, S. H. Ferreira, et al. Peroxisome Proliferator-Activated Receptor-{gamma} Ligand, 15-Deoxy-{Delta}12,14-Prostaglandin J2, Reduces Neutrophil Migration via a Nitric Oxide Pathway J. Immunol., January 1, 2008; 180(1): 609 - 617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Harada, V. N. Lama, L. N. Badri, T. Ohtsuka, D. Petrovic-Djergovic, H. Liao, Y. Yoshikawa, K. Iwanaga, C. L. Lau, and D. J. Pinsky Early growth response gene-1 promotes airway allograft rejection Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L124 - L130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Muranaka, Y. Yanagi, Y. Tamaki, T. Usui, N. Kubota, A. Iriyama, Y. Terauchi, T. Kadowaki, and M. Araie Effects of Peroxisome Proliferator-Activated Receptor {gamma} and Its Ligand on Blood-Retinal Barrier in a Streptozotocin-Induced Diabetic Model. Invest. Ophthalmol. Vis. Sci., October 1, 2006; 47(10): 4547 - 4552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Rogler Significance of anti-inflammatory effects of PPAR{gamma} agonists? Gut, August 1, 2006; 55(8): 1067 - 1069. [Full Text] [PDF]
|
|
|
|
 |
|
 S.-J. Chen, H. Ning, W. Ishida, S. Sodin-Semrl, S. Takagawa, Y. Mori, and J. Varga The Early-Immediate Gene EGR-1 Is Induced by Transforming Growth Factor-beta and Mediates Stimulation of Collagen Gene Expression J. Biol. Chem., July 28, 2006; 281(30): 21183 - 21197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Lee, J. Frischer, A. Serur, J. Huang, J.-O Bae, Z. N. Kornfield, L. Eljuga, C. J. Shawber, N. Feirt, M. Mansukhani, et al. Inhibition of cyclooxygenase-2 disrupts tumor vascular mural cell recruitment and survival signaling. Cancer Res., April 15, 2006; 66(8): 4378 - 4384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Wang, Z. Zhou, M. Zhang, L. Fan, F. Forudi, X. Zhou, W. Qu, A. M. Lincoff, A. M. Schmidt, E. J. Topol, et al. Peroxisome Proliferator-Activated Receptor {gamma} Down-Regulates Receptor for Advanced Glycation End Products and Inhibits Smooth Muscle Cell Proliferation in a Diabetic and Nondiabetic Rat Carotid Artery Injury Model J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 37 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Standiford, V. G. Keshamouni, and R. C. Reddy Peroxisome Proliferator-activated Receptor-{gamma} as a Regulator of Lung Inflammation and Repair Proceedings of the ATS, October 1, 2005; 2(3): 226 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Abdelrahman, A. Sivarajah, and C. Thiemermann Beneficial effects of PPAR-{gamma} ligands in ischemia-reperfusion injury, inflammation and shock Cardiovasc Res, March 1, 2005; 65(4): 772 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Xu, M. Gen, L. Lu, J. Fox, S. O. Weiss, R. D. Brown, D. Perlov, H. Ahmad, P. Zhu, C. Greyson, et al. PPAR-{gamma} activation fails to provide myocardial protection in ischemia and reperfusion in pigs Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1314 - H1323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Sung, S. Park, B. P. Yu, and H. Y. Chung Modulation of PPAR in Aging, Inflammation, and Calorie Restriction J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2004; 59(10): B997 - B1006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Cheng, H. Afif, J. Martel-Pelletier, J.-P. Pelletier, X. Li, K. Farrajota, M. Lavigne, and H. Fahmi Activation of Peroxisome Proliferator-activated Receptor {gamma} Inhibits Interleukin-1{beta}-induced Membrane-associated Prostaglandin E2 Synthase-1 Expression in Human Synovial Fibroblasts by Interfering with Egr-1 J. Biol. Chem., May 21, 2004; 279(21): 22057 - 22065. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
