Selected Publications by Rutgers University Investigators using the Core Facility
2018
Chen, Xuguang; Nomani, Alireza; Patel, Niket; Nouri, Faranak S; Hatefi, Arash
Bioengineering a non-genotoxic vector for genetic modification of mesenchymal stem cells Journal Article
In: Biomaterials, vol. 152, pp. 1–14, 2018, ISSN: 1878-5905.
@article{pmid29078136,
title = {Bioengineering a non-genotoxic vector for genetic modification of mesenchymal stem cells},
author = {Xuguang Chen and Alireza Nomani and Niket Patel and Faranak S Nouri and Arash Hatefi},
doi = {10.1016/j.biomaterials.2017.10.028},
issn = {1878-5905},
year = {2018},
date = {2018-01-01},
journal = {Biomaterials},
volume = {152},
pages = {1--14},
abstract = {Vectors used for stem cell transfection must be non-genotoxic, in addition to possessing high efficiency, because they could potentially transform normal stem cells into cancer-initiating cells. The objective of this research was to bioengineer an efficient vector that can be used for genetic modification of stem cells without any negative somatic or genetic impact. Two types of multifunctional vectors, namely targeted and non-targeted were genetically engineered and purified from E. coli. The targeted vectors were designed to enter stem cells via overexpressed receptors. The non-targeted vectors were equipped with MPG and Pep1 cell penetrating peptides. A series of commercial synthetic non-viral vectors and an adenoviral vector were used as controls. All vectors were evaluated for their efficiency and impact on metabolic activity, cell membrane integrity, chromosomal aberrations (micronuclei formation), gene dysregulation, and differentiation ability of stem cells. The results of this study showed that the bioengineered vector utilizing VEGFR-1 receptors for cellular entry could transfect mesenchymal stem cells with high efficiency without inducing genotoxicity, negative impact on gene function, or ability to differentiate. Overall, the vectors that utilized receptors as ports for cellular entry (viral and non-viral) showed considerably better somato- and genosafety profiles in comparison to those that entered through electrostatic interaction with cellular membrane. The genetically engineered vector in this study demonstrated that it can be safely and efficiently used to genetically modify stem cells with potential applications in tissue engineering and cancer therapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Vectors used for stem cell transfection must be non-genotoxic, in addition to possessing high efficiency, because they could potentially transform normal stem cells into cancer-initiating cells. The objective of this research was to bioengineer an efficient vector that can be used for genetic modification of stem cells without any negative somatic or genetic impact. Two types of multifunctional vectors, namely targeted and non-targeted were genetically engineered and purified from E. coli. The targeted vectors were designed to enter stem cells via overexpressed receptors. The non-targeted vectors were equipped with MPG and Pep1 cell penetrating peptides. A series of commercial synthetic non-viral vectors and an adenoviral vector were used as controls. All vectors were evaluated for their efficiency and impact on metabolic activity, cell membrane integrity, chromosomal aberrations (micronuclei formation), gene dysregulation, and differentiation ability of stem cells. The results of this study showed that the bioengineered vector utilizing VEGFR-1 receptors for cellular entry could transfect mesenchymal stem cells with high efficiency without inducing genotoxicity, negative impact on gene function, or ability to differentiate. Overall, the vectors that utilized receptors as ports for cellular entry (viral and non-viral) showed considerably better somato- and genosafety profiles in comparison to those that entered through electrostatic interaction with cellular membrane. The genetically engineered vector in this study demonstrated that it can be safely and efficiently used to genetically modify stem cells with potential applications in tissue engineering and cancer therapy.
2017
Francis, Mary; Groves, Angela M; Sun, Richard; Cervelli, Jessica A; Choi, Hyejeong; Laskin, Jeffrey D; Laskin, Debra L
Editor's Highlight: CCR2 Regulates Inflammatory Cell Accumulation in the Lung and Tissue Injury following Ozone Exposure Journal Article
In: Toxicol Sci, vol. 155, no. 2, pp. 474–484, 2017, ISSN: 1096-0929.
@article{pmid27837169,
title = {Editor's Highlight: CCR2 Regulates Inflammatory Cell Accumulation in the Lung and Tissue Injury following Ozone Exposure},
author = {Mary Francis and Angela M Groves and Richard Sun and Jessica A Cervelli and Hyejeong Choi and Jeffrey D Laskin and Debra L Laskin},
doi = {10.1093/toxsci/kfw226},
issn = {1096-0929},
year = {2017},
date = {2017-01-01},
journal = {Toxicol Sci},
volume = {155},
number = {2},
pages = {474--484},
abstract = {Ozone-induced lung injury is associated with an accumulation of activated macrophages in the lung. Chemokine receptor CCR2 mediates the migration of inflammatory monocytes/macrophages to sites of tissue injury. It is also required for monocyte egress from the bone marrow. In the present studies, we analyzed the role of CCR2 in inflammatory cell trafficking to the lung in response to ozone. Treatment of mice with ozone (0.8 ppm, 3 h) resulted in increases in proinflammatory CCR2 macrophages in the lung at 24 h, as well as proinflammatory CD11b Ly6C and iNOS macrophages at 24 and 48 h. Mannose receptor anti-inflammatory macrophages were also observed in the lung 24 and 48 h post-ozone. Loss of CCR2 was associated with reduced numbers of proinflammatory macrophages in the lung and decreased expression of the proinflammatory cytokines, IL-1β and TNFα. Decreases in anti-inflammatory CD11b Ly6C macrophages were also observed in lungs of CCR2 mice treated with ozone, whereas mannose receptormacrophage accumulation was delayed; conversely, CX3CL1 and CX3CR1 were upregulated. Changes in lung macrophage subpopulations and inflammatory gene expression in CCR2 mice were correlated with reduced ozone toxicity and oxidative stress, as measured by decreases in bronchoalveolar lavage protein content and reduced lung expression of heme-oxygenase-1, 4-hydroxynonenal and cytochrome b5. These data demonstrate that CCR2 plays a role in both pro- and anti-inflammatory macrophage accumulation in the lung following ozone exposure. The fact that ozone-induced lung injury and oxidative stress are reduced in CCR2 mice suggests more prominent effects on proinflammatory macrophages.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Ozone-induced lung injury is associated with an accumulation of activated macrophages in the lung. Chemokine receptor CCR2 mediates the migration of inflammatory monocytes/macrophages to sites of tissue injury. It is also required for monocyte egress from the bone marrow. In the present studies, we analyzed the role of CCR2 in inflammatory cell trafficking to the lung in response to ozone. Treatment of mice with ozone (0.8 ppm, 3 h) resulted in increases in proinflammatory CCR2 macrophages in the lung at 24 h, as well as proinflammatory CD11b Ly6C and iNOS macrophages at 24 and 48 h. Mannose receptor anti-inflammatory macrophages were also observed in the lung 24 and 48 h post-ozone. Loss of CCR2 was associated with reduced numbers of proinflammatory macrophages in the lung and decreased expression of the proinflammatory cytokines, IL-1β and TNFα. Decreases in anti-inflammatory CD11b Ly6C macrophages were also observed in lungs of CCR2 mice treated with ozone, whereas mannose receptormacrophage accumulation was delayed; conversely, CX3CL1 and CX3CR1 were upregulated. Changes in lung macrophage subpopulations and inflammatory gene expression in CCR2 mice were correlated with reduced ozone toxicity and oxidative stress, as measured by decreases in bronchoalveolar lavage protein content and reduced lung expression of heme-oxygenase-1, 4-hydroxynonenal and cytochrome b5. These data demonstrate that CCR2 plays a role in both pro- and anti-inflammatory macrophage accumulation in the lung following ozone exposure. The fact that ozone-induced lung injury and oxidative stress are reduced in CCR2 mice suggests more prominent effects on proinflammatory macrophages.
Francis, Mary; Sun, Richard; Cervelli, Jessica A; Choi, Hyejeong; Mandal, Mili; Abramova, Elena V; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L
Editor's Highlight: Role of Spleen-Derived Macrophages in Ozone-Induced Lung Inflammation and Injury Journal Article
In: Toxicol Sci, vol. 155, no. 1, pp. 182–195, 2017, ISSN: 1096-0929.
@article{pmid27708193,
title = {Editor's Highlight: Role of Spleen-Derived Macrophages in Ozone-Induced Lung Inflammation and Injury},
author = {Mary Francis and Richard Sun and Jessica A Cervelli and Hyejeong Choi and Mili Mandal and Elena V Abramova and Andrew J Gow and Jeffrey D Laskin and Debra L Laskin},
doi = {10.1093/toxsci/kfw192},
issn = {1096-0929},
year = {2017},
date = {2017-01-01},
journal = {Toxicol Sci},
volume = {155},
number = {1},
pages = {182--195},
abstract = {Macrophages and inflammatory mediators have been implicated in ozone toxicity. In these studies, we used splenectomized (SPX) mice to assess the contribution of splenic monocytes to pulmonary inflammation and injury induced by ozone. Cells and tissue were collected 24-72 h after exposure of mice to air or ozone (0.8 ppm, 3 h). Following ozone exposure, increased numbers of pro-inflammatory CD11b Ly6C and anti-inflammatory CD11b Ly6C monocytes were observed in spleens of control (CTL) mice. CD11b Ly6C and MMP-9pro-inflammatory macrophages were also observed in lungs of CTL mice after ozone, along with CD11b Ly6C and mannose receptor (MR) anti-inflammatory macrophages. This was accompanied by increased lung expression of proteins involved in monocyte/macrophage trafficking including CCL3, CCL4, CCR1, and AT1R. Splenectomy resulted in decreases in pro-inflammatory macrophages in the lung and down regulation of CCR2, CCL2, and CCL4, but increases in CD11b Ly6C anti-inflammatory macrophages. CD11bLy6GLy6C granulocytic (G)- and monocytic (M)-myeloid derived suppressor cells (MDSC)s were also detected in the lungs and spleens of CTL mice; these increased after ozone exposure. Splenectomy was associated with a decrease in G-MDSCs in the lung, with no effect on M-MDSCs. Changes in lung macrophage subpopulations and MDSCs in SPX mice were correlated with reduced ozone toxicity, as measured by decreases in bronchoalveolar lavage protein content and reduced 4-hydroxynonenal expression in the lung. These data suggest that the spleen is a source of pro-inflammatory/cytotoxic macrophages that contribute to ozone-induced lung injury, inflammation, and oxidative stress.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Macrophages and inflammatory mediators have been implicated in ozone toxicity. In these studies, we used splenectomized (SPX) mice to assess the contribution of splenic monocytes to pulmonary inflammation and injury induced by ozone. Cells and tissue were collected 24-72 h after exposure of mice to air or ozone (0.8 ppm, 3 h). Following ozone exposure, increased numbers of pro-inflammatory CD11b Ly6C and anti-inflammatory CD11b Ly6C monocytes were observed in spleens of control (CTL) mice. CD11b Ly6C and MMP-9pro-inflammatory macrophages were also observed in lungs of CTL mice after ozone, along with CD11b Ly6C and mannose receptor (MR) anti-inflammatory macrophages. This was accompanied by increased lung expression of proteins involved in monocyte/macrophage trafficking including CCL3, CCL4, CCR1, and AT1R. Splenectomy resulted in decreases in pro-inflammatory macrophages in the lung and down regulation of CCR2, CCL2, and CCL4, but increases in CD11b Ly6C anti-inflammatory macrophages. CD11bLy6GLy6C granulocytic (G)- and monocytic (M)-myeloid derived suppressor cells (MDSC)s were also detected in the lungs and spleens of CTL mice; these increased after ozone exposure. Splenectomy was associated with a decrease in G-MDSCs in the lung, with no effect on M-MDSCs. Changes in lung macrophage subpopulations and MDSCs in SPX mice were correlated with reduced ozone toxicity, as measured by decreases in bronchoalveolar lavage protein content and reduced 4-hydroxynonenal expression in the lung. These data suggest that the spleen is a source of pro-inflammatory/cytotoxic macrophages that contribute to ozone-induced lung injury, inflammation, and oxidative stress.
2016
Venosa, Alessandro; Malaviya, Rama; Choi, Hyejeong; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L
Characterization of Distinct Macrophage Subpopulations during Nitrogen Mustard-Induced Lung Injury and Fibrosis Journal Article
In: Am J Respir Cell Mol Biol, vol. 54, no. 3, pp. 436–446, 2016, ISSN: 1535-4989.
@article{pmid26273949,
title = {Characterization of Distinct Macrophage Subpopulations during Nitrogen Mustard-Induced Lung Injury and Fibrosis},
author = {Alessandro Venosa and Rama Malaviya and Hyejeong Choi and Andrew J Gow and Jeffrey D Laskin and Debra L Laskin},
doi = {10.1165/rcmb.2015-0120OC},
issn = {1535-4989},
year = {2016},
date = {2016-03-01},
journal = {Am J Respir Cell Mol Biol},
volume = {54},
number = {3},
pages = {436--446},
abstract = {Nitrogen mustard (NM) is an alkylating agent known to cause extensive pulmonary injury progressing to fibrosis. This is accompanied by a persistent macrophage inflammatory response. In these studies, we characterized the phenotype of macrophages accumulating in the lung over time following NM exposure. Treatment of rats with NM (0.125 mg/kg, intratracheally) resulted in an increase in CD11b(+) macrophages in histologic sections. These cells consisted of inducible nitric oxide synthase(+) (iNOS) proinflammatory M1 macrophages, and CD68(+), CD163(+), CD206(+), YM-1(+), and arginase-II(+)antiinflammatory M2 macrophages. Although M1 macrophages were prominent 1-3 days after NM, M2 macrophages were most notable at 28 days. At this time, they were enlarged and vacuolated, consistent with a profibrotic phenotype. Flow cytometric analysis of isolated lung macrophages identified three phenotypically distinct subpopulations: mature CD11b(-), CD43(-), and CD68(+) resident macrophages, which decreased in numbers after NM; and two infiltrating (CD11b(+)) macrophage subsets: immature CD43(+) M1 macrophages and mature CD43(-) M2 macrophages, which increased sequentially. Time-related increases in M1 (iNOS, IL-12α, COX-2, TNF-α, matrix metalloproteinase-9, matrix metalloproteinase-10) and M2 (IL-10, pentraxin-2, connective tissue growth factor, ApoE) genes, as well as chemokines/chemokine receptors associated with trafficking of M1 (CCR2, CCR5, CCL2, CCL5) and M2 (CX3CR1, fractalkine) macrophages to sites of injury, were also noted in macrophages isolated from the lung after NM. The appearance of M1 and M2 macrophages in the lung correlated with NM-induced acute injury and the development of fibrosis, suggesting a potential role of these macrophage subpopulations in the pathogenic response to NM. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Nitrogen mustard (NM) is an alkylating agent known to cause extensive pulmonary injury progressing to fibrosis. This is accompanied by a persistent macrophage inflammatory response. In these studies, we characterized the phenotype of macrophages accumulating in the lung over time following NM exposure. Treatment of rats with NM (0.125 mg/kg, intratracheally) resulted in an increase in CD11b(+) macrophages in histologic sections. These cells consisted of inducible nitric oxide synthase(+) (iNOS) proinflammatory M1 macrophages, and CD68(+), CD163(+), CD206(+), YM-1(+), and arginase-II(+)antiinflammatory M2 macrophages. Although M1 macrophages were prominent 1-3 days after NM, M2 macrophages were most notable at 28 days. At this time, they were enlarged and vacuolated, consistent with a profibrotic phenotype. Flow cytometric analysis of isolated lung macrophages identified three phenotypically distinct subpopulations: mature CD11b(-), CD43(-), and CD68(+) resident macrophages, which decreased in numbers after NM; and two infiltrating (CD11b(+)) macrophage subsets: immature CD43(+) M1 macrophages and mature CD43(-) M2 macrophages, which increased sequentially. Time-related increases in M1 (iNOS, IL-12α, COX-2, TNF-α, matrix metalloproteinase-9, matrix metalloproteinase-10) and M2 (IL-10, pentraxin-2, connective tissue growth factor, ApoE) genes, as well as chemokines/chemokine receptors associated with trafficking of M1 (CCR2, CCR5, CCL2, CCL5) and M2 (CX3CR1, fractalkine) macrophages to sites of injury, were also noted in macrophages isolated from the lung after NM. The appearance of M1 and M2 macrophages in the lung correlated with NM-induced acute injury and the development of fibrosis, suggesting a potential role of these macrophage subpopulations in the pathogenic response to NM.
Mandal, Mili; Gardner, Carol R; Sun, Richard; Choi, Hyejeong; Lad, Sonali; Mishin, Vladimir; Laskin, Jeffrey D; Laskin, Debra L
The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury Journal Article
In: Toxicol Appl Pharmacol, vol. 304, pp. 110–120, 2016, ISSN: 1096-0333.
@article{pmid27163765,
title = {The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury},
author = {Mili Mandal and Carol R Gardner and Richard Sun and Hyejeong Choi and Sonali Lad and Vladimir Mishin and Jeffrey D Laskin and Debra L Laskin},
doi = {10.1016/j.taap.2016.04.019},
issn = {1096-0333},
year = {2016},
date = {2016-01-01},
journal = {Toxicol Appl Pharmacol},
volume = {304},
pages = {110--120},
abstract = {Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300mg/kg, i.p.) to control mice resulted in an increase in CD11b(+) infiltrating Ly6G(+) granulocytic and Ly6G(-) monocytic cells in the spleen and the liver. The majority of the Ly6G(+) cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G(-) cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80(+)) and immature (F4/80(-)) pro-inflammatory Ly6C(hi) macrophages and mature anti-inflammatory (Ly6C(lo)) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3(+) macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300mg/kg, i.p.) to control mice resulted in an increase in CD11b(+) infiltrating Ly6G(+) granulocytic and Ly6G(-) monocytic cells in the spleen and the liver. The majority of the Ly6G(+) cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G(-) cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80(+)) and immature (F4/80(-)) pro-inflammatory Ly6C(hi) macrophages and mature anti-inflammatory (Ly6C(lo)) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3(+) macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs.
2015
Sunil, Vasanthi R; Francis, Mary; Vayas, Kinal N; Cervelli, Jessica A; Choi, Hyejeong; Laskin, Jeffrey D; Laskin, Debra L
Regulation of ozone-induced lung inflammation and injury by the β-galactoside-binding lectin galectin-3 Journal Article
In: Toxicol Appl Pharmacol, vol. 284, no. 2, pp. 236–245, 2015, ISSN: 1096-0333.
@article{pmid25724551,
title = {Regulation of ozone-induced lung inflammation and injury by the β-galactoside-binding lectin galectin-3},
author = {Vasanthi R Sunil and Mary Francis and Kinal N Vayas and Jessica A Cervelli and Hyejeong Choi and Jeffrey D Laskin and Debra L Laskin},
doi = {10.1016/j.taap.2015.02.002},
issn = {1096-0333},
year = {2015},
date = {2015-04-01},
journal = {Toxicol Appl Pharmacol},
volume = {284},
number = {2},
pages = {236--245},
abstract = {Macrophages play a dual role in ozone toxicity, contributing to both pro- and anti-inflammatory processes. Galectin-3 (Gal-3) is a lectin known to regulate macrophage activity. Herein, we analyzed the role of Gal-3 in the response of lung macrophages to ozone. Bronchoalveolar lavage (BAL) and lung tissue were collected 24-72h after exposure (3h) of WT and Gal-3(-/-) mice to air or 0.8ppm ozone. In WT mice, ozone inhalation resulted in increased numbers of proinflammatory (Gal-3(+), iNOS(+)) and anti-inflammatory (MR-1(+)) macrophages in the lungs. While accumulation of iNOS(+) macrophages was attenuated in Gal-3(-/-) mice, increased numbers of enlarged MR-1(+) macrophages were noted. This correlated with increased numbers of macrophages in BAL. Flow cytometric analysis showed that these cells were CD11b(+) and consisted mainly (>97%) of mature (F4/80(+)CD11c(+)) proinflammatory (Ly6GLy6C(hi)) and anti-inflammatory (Ly6GLy6C(lo)) macrophages. Increases in both macrophage subpopulations were observed following ozone inhalation. Loss of Gal-3 resulted in a decrease in Ly6C(hi) macrophages, with no effect on Ly6C(lo) macrophages. CD11b(+)Ly6G(+)Ly6C(+) granulocytic (G) and monocytic (M) myeloid derived suppressor cells (MDSC) were also identified in the lung after ozone. In Gal-3(-/-) mice, the response of G-MDSC to ozone was attenuated, while the response of M-MDSC was heightened. Changes in inflammatory cell populations in the lung of ozone treated Gal-3(-/-) mice were correlated with reduced tissue injury as measured by cytochrome b5 expression. These data demonstrate that Gal-3 plays a role in promoting proinflammatory macrophage accumulation and toxicity in the lung following ozone exposure. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Macrophages play a dual role in ozone toxicity, contributing to both pro- and anti-inflammatory processes. Galectin-3 (Gal-3) is a lectin known to regulate macrophage activity. Herein, we analyzed the role of Gal-3 in the response of lung macrophages to ozone. Bronchoalveolar lavage (BAL) and lung tissue were collected 24-72h after exposure (3h) of WT and Gal-3(-/-) mice to air or 0.8ppm ozone. In WT mice, ozone inhalation resulted in increased numbers of proinflammatory (Gal-3(+), iNOS(+)) and anti-inflammatory (MR-1(+)) macrophages in the lungs. While accumulation of iNOS(+) macrophages was attenuated in Gal-3(-/-) mice, increased numbers of enlarged MR-1(+) macrophages were noted. This correlated with increased numbers of macrophages in BAL. Flow cytometric analysis showed that these cells were CD11b(+) and consisted mainly (>97%) of mature (F4/80(+)CD11c(+)) proinflammatory (Ly6GLy6C(hi)) and anti-inflammatory (Ly6GLy6C(lo)) macrophages. Increases in both macrophage subpopulations were observed following ozone inhalation. Loss of Gal-3 resulted in a decrease in Ly6C(hi) macrophages, with no effect on Ly6C(lo) macrophages. CD11b(+)Ly6G(+)Ly6C(+) granulocytic (G) and monocytic (M) myeloid derived suppressor cells (MDSC) were also identified in the lung after ozone. In Gal-3(-/-) mice, the response of G-MDSC to ozone was attenuated, while the response of M-MDSC was heightened. Changes in inflammatory cell populations in the lung of ozone treated Gal-3(-/-) mice were correlated with reduced tissue injury as measured by cytochrome b5 expression. These data demonstrate that Gal-3 plays a role in promoting proinflammatory macrophage accumulation and toxicity in the lung following ozone exposure.
2012
Dragomir, Ana-Cristina Docan; Sun, Richard; Choi, Hyejeong; Laskin, Jeffrey D; Laskin, Debra L
Role of galectin-3 in classical and alternative macrophage activation in the liver following acetaminophen intoxication Journal Article
In: J Immunol, vol. 189, no. 12, pp. 5934–5941, 2012, ISSN: 1550-6606.
@article{pmid23175698,
title = {Role of galectin-3 in classical and alternative macrophage activation in the liver following acetaminophen intoxication},
author = {Ana-Cristina Docan Dragomir and Richard Sun and Hyejeong Choi and Jeffrey D Laskin and Debra L Laskin},
doi = {10.4049/jimmunol.1201851},
issn = {1550-6606},
year = {2012},
date = {2012-12-01},
journal = {J Immunol},
volume = {189},
number = {12},
pages = {5934--5941},
abstract = {Inflammatory macrophages have been implicated in hepatotoxicity induced by the analgesic acetaminophen (APAP). In these studies, we characterized the phenotype of macrophages accumulating in the liver following APAP intoxication and evaluated the role of galectin-3 (Gal-3) in macrophage activation. Administration of APAP (300 mg/kg, i.p.) to wild-type mice resulted in the appearance of two distinct subpopulations of CD11b(+) cells in the liver, which expressed high or low levels of the monocyte/macrophage activation marker Ly6C. Whereas CD11b(+)/Ly6C(hi) macrophages exhibited a classically activated proinflammatory phenotype characterized by increased expression of TNF-α, inducible NO synthase, and CCR2, CD11b(+)/Ly6C(lo) macrophages were alternatively activated, expressing high levels of the anti-inflammatory cytokine IL-10. APAP intoxication was also associated with an accumulation of Gal-3(+) macrophages in the liver; the majority of these cells were Ly6C(hi). APAP-induced increases in CD11b(+)/Ly6C(hi) macrophages were significantly reduced in Gal-3(-/-) mice. This reduction was evident 72 h post APAP and was correlated with decreased expression of the classical macrophage activation markers, inducible NO synthase, IL-12, and TNF-α, as well as the proinflammatory chemokines CCL2 and CCL3, and chemokine receptors CCR1 and CCR2. Conversely, numbers of CD11b(+)/Ly6C(lo) macrophages increased in livers of APAP-treated Gal-3(-/-) mice; this was associated with increased expression of the alternative macrophage activation markers Ym1 and Fizz1, increased liver repair, and reduced hepatotoxicity. These data demonstrate that both classically and alternatively activated macrophages accumulate in the liver following APAP intoxication; moreover, Gal-3 plays a role in promoting a persistent proinflammatory macrophage phenotype.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Inflammatory macrophages have been implicated in hepatotoxicity induced by the analgesic acetaminophen (APAP). In these studies, we characterized the phenotype of macrophages accumulating in the liver following APAP intoxication and evaluated the role of galectin-3 (Gal-3) in macrophage activation. Administration of APAP (300 mg/kg, i.p.) to wild-type mice resulted in the appearance of two distinct subpopulations of CD11b(+) cells in the liver, which expressed high or low levels of the monocyte/macrophage activation marker Ly6C. Whereas CD11b(+)/Ly6C(hi) macrophages exhibited a classically activated proinflammatory phenotype characterized by increased expression of TNF-α, inducible NO synthase, and CCR2, CD11b(+)/Ly6C(lo) macrophages were alternatively activated, expressing high levels of the anti-inflammatory cytokine IL-10. APAP intoxication was also associated with an accumulation of Gal-3(+) macrophages in the liver; the majority of these cells were Ly6C(hi). APAP-induced increases in CD11b(+)/Ly6C(hi) macrophages were significantly reduced in Gal-3(-/-) mice. This reduction was evident 72 h post APAP and was correlated with decreased expression of the classical macrophage activation markers, inducible NO synthase, IL-12, and TNF-α, as well as the proinflammatory chemokines CCL2 and CCL3, and chemokine receptors CCR1 and CCR2. Conversely, numbers of CD11b(+)/Ly6C(lo) macrophages increased in livers of APAP-treated Gal-3(-/-) mice; this was associated with increased expression of the alternative macrophage activation markers Ym1 and Fizz1, increased liver repair, and reduced hepatotoxicity. These data demonstrate that both classically and alternatively activated macrophages accumulate in the liver following APAP intoxication; moreover, Gal-3 plays a role in promoting a persistent proinflammatory macrophage phenotype.
2011
Chao, Ming-Wei; Kozlosky, John; Po, Iris P; Strickland, Pamela Ohman; Svoboda, Kathy K H; Cooper, Keith; Laumbach, Robert J; Gordon, Marion K
Diesel exhaust particle exposure causes redistribution of endothelial tube VE-cadherin Journal Article
In: Toxicology, vol. 279, no. 1-3, pp. 73–84, 2011, ISSN: 1879-3185.
@article{pmid20887764,
title = {Diesel exhaust particle exposure causes redistribution of endothelial tube VE-cadherin},
author = {Ming-Wei Chao and John Kozlosky and Iris P Po and Pamela Ohman Strickland and Kathy K H Svoboda and Keith Cooper and Robert J Laumbach and Marion K Gordon},
doi = {10.1016/j.tox.2010.09.011},
issn = {1879-3185},
year = {2011},
date = {2011-01-01},
journal = {Toxicology},
volume = {279},
number = {1-3},
pages = {73--84},
abstract = {Whether diesel exhaust particles (DEPs) potentially have a direct effect on capillary endothelia was examined by following the adherens junction component, vascular endothelial cell cadherin (VE-cadherin). This molecule is incorporated into endothelial adherens junctions at the cell surface, where it forms homodimeric associations with adjacent cells and contributes to the barrier function of the vasculature (Dejana et al., 2008; Venkiteswaran et al., 2002; Villasante et al., 2007). Human umbilical vein endothelial cells (HUVECs) that were pre-formed into capillary-like tube networks in vitro were exposed to DEPs for 24h. After exposure, the integrity of VE-cadherin in adherens junctions was assessed by immunofluorescence analysis, and demonstrated that increasing concentrations of DEPs caused increasing redistribution of VE-cadherin away from the cell-cell junctions toward intracellular locations. Since HUVEC tube networks are three-dimensional structures, whether particles entered the endothelial cells or tubular lumens was also examined. The data indicate that translocation of the particles does occur. The results, obtained in a setting that removes the confounding effects of inflammatory cells or blood components, suggest that if DEPs encounter alveolar capillaries in vivo, they may be able to directly affect the endothelial cell-cell junctions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Whether diesel exhaust particles (DEPs) potentially have a direct effect on capillary endothelia was examined by following the adherens junction component, vascular endothelial cell cadherin (VE-cadherin). This molecule is incorporated into endothelial adherens junctions at the cell surface, where it forms homodimeric associations with adjacent cells and contributes to the barrier function of the vasculature (Dejana et al., 2008; Venkiteswaran et al., 2002; Villasante et al., 2007). Human umbilical vein endothelial cells (HUVECs) that were pre-formed into capillary-like tube networks in vitro were exposed to DEPs for 24h. After exposure, the integrity of VE-cadherin in adherens junctions was assessed by immunofluorescence analysis, and demonstrated that increasing concentrations of DEPs caused increasing redistribution of VE-cadherin away from the cell-cell junctions toward intracellular locations. Since HUVEC tube networks are three-dimensional structures, whether particles entered the endothelial cells or tubular lumens was also examined. The data indicate that translocation of the particles does occur. The results, obtained in a setting that removes the confounding effects of inflammatory cells or blood components, suggest that if DEPs encounter alveolar capillaries in vivo, they may be able to directly affect the endothelial cell-cell junctions.
2010
Vetrano, Anna M; Laskin, Debra L; Archer, Faith; Syed, Kirin; Gray, Joshua P; Laskin, Jeffrey D; Nwebube, Nkiru; Weinberger, Barry
Inflammatory effects of phthalates in neonatal neutrophils Journal Article
In: Pediatr Res, vol. 68, no. 2, pp. 134–139, 2010, ISSN: 1530-0447.
@article{pmid20453712,
title = {Inflammatory effects of phthalates in neonatal neutrophils},
author = {Anna M Vetrano and Debra L Laskin and Faith Archer and Kirin Syed and Joshua P Gray and Jeffrey D Laskin and Nkiru Nwebube and Barry Weinberger},
doi = {10.1203/PDR.0b013e3181e5c1f7},
issn = {1530-0447},
year = {2010},
date = {2010-08-01},
journal = {Pediatr Res},
volume = {68},
number = {2},
pages = {134--139},
abstract = {Hospitalized infants are exposed to numerous devices containing the plasticizer di-(2-ethylhexyl) phthalate. Urinary levels of the phthalate metabolite, mono-(2-ethylhexyl) phthalate (MEHP), are markedly elevated in premature infants. Phthalates inactivate peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear transcription factor that mediates the resolution of inflammation, a process impaired in neonates. We speculate that this increases their susceptibility to MEHP, and this was analyzed. MEHP inhibited neutrophil apoptosis; neonatal cells were more sensitive than adult cells. In neonatal, but not in adult neutrophils, MEHP also inhibited chemotaxis, stimulated oxidative metabolism, and up-regulated expression of NADPH oxidase-1. In both adult and neonatal neutrophils, MEHP stimulated IL-1beta and VEGF production, whereas IL-8 production was stimulated only in adult cells. In contrast, MEHP-inhibited production of MIP-1beta by adult cells, and Regulated on Activation Normal T Cell Expressed and Secreted (RANTES) by neonatal neutrophils. The effects of MEHP on apoptosis and oxidative metabolism in neonatal cells were reversed by the PPAR-gamma agonist, troglitazone. Whereas troglitazone had no effect on MEHP-induced alterations in inflammatory protein or chemokine production, constitutive IL-8 and MIP-1beta production was reduced in adult neutrophils, and RANTES and MIP-1beta in neonatal cells. These findings suggest that neonatal neutrophils are more sensitive to phthalate-mediated inhibition of PPAR-gamma, which may be related to decreased anti-inflammatory signaling.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hospitalized infants are exposed to numerous devices containing the plasticizer di-(2-ethylhexyl) phthalate. Urinary levels of the phthalate metabolite, mono-(2-ethylhexyl) phthalate (MEHP), are markedly elevated in premature infants. Phthalates inactivate peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear transcription factor that mediates the resolution of inflammation, a process impaired in neonates. We speculate that this increases their susceptibility to MEHP, and this was analyzed. MEHP inhibited neutrophil apoptosis; neonatal cells were more sensitive than adult cells. In neonatal, but not in adult neutrophils, MEHP also inhibited chemotaxis, stimulated oxidative metabolism, and up-regulated expression of NADPH oxidase-1. In both adult and neonatal neutrophils, MEHP stimulated IL-1beta and VEGF production, whereas IL-8 production was stimulated only in adult cells. In contrast, MEHP-inhibited production of MIP-1beta by adult cells, and Regulated on Activation Normal T Cell Expressed and Secreted (RANTES) by neonatal neutrophils. The effects of MEHP on apoptosis and oxidative metabolism in neonatal cells were reversed by the PPAR-gamma agonist, troglitazone. Whereas troglitazone had no effect on MEHP-induced alterations in inflammatory protein or chemokine production, constitutive IL-8 and MIP-1beta production was reduced in adult neutrophils, and RANTES and MIP-1beta in neonatal cells. These findings suggest that neonatal neutrophils are more sensitive to phthalate-mediated inhibition of PPAR-gamma, which may be related to decreased anti-inflammatory signaling.
Fong, Dunne; Yeh, Arthur; Naftalovich, Rotem; Choi, Theresa Hyejeong; Chan, Marion M
Curcumin inhibits the side population (SP) phenotype of the rat C6 glioma cell line: towards targeting of cancer stem cells with phytochemicals Journal Article
In: Cancer Lett, vol. 293, no. 1, pp. 65–72, 2010, ISSN: 1872-7980.
@article{pmid20089354,
title = {Curcumin inhibits the side population (SP) phenotype of the rat C6 glioma cell line: towards targeting of cancer stem cells with phytochemicals},
author = {Dunne Fong and Arthur Yeh and Rotem Naftalovich and Theresa Hyejeong Choi and Marion M Chan},
doi = {10.1016/j.canlet.2009.12.018},
issn = {1872-7980},
year = {2010},
date = {2010-07-01},
journal = {Cancer Lett},
volume = {293},
number = {1},
pages = {65--72},
abstract = {The phytochemical curcumin, from the Indian spice turmeric, has many biological properties, including anti-inflammatory and anti-carcinogenic activities. We have examined the effects of curcumin on the rat C6 glioma cell line. Treated and control cells were analyzed by Hoechst 33342 dye and flow cytometry. We observed a decrease in the side population (SP) of C6 cells after daily curcumin treatment of the C6 cells. Direct incubation of curcumin to C6 cells during the Hoechst assay also decreased SP. Since SP has been associated with stem cell populations, curcumin may be a dietary phytochemical with potential to target cancer stem cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The phytochemical curcumin, from the Indian spice turmeric, has many biological properties, including anti-inflammatory and anti-carcinogenic activities. We have examined the effects of curcumin on the rat C6 glioma cell line. Treated and control cells were analyzed by Hoechst 33342 dye and flow cytometry. We observed a decrease in the side population (SP) of C6 cells after daily curcumin treatment of the C6 cells. Direct incubation of curcumin to C6 cells during the Hoechst assay also decreased SP. Since SP has been associated with stem cell populations, curcumin may be a dietary phytochemical with potential to target cancer stem cells.
Garbuzenko, Olga B; Saad, Maha; Pozharov, Vitaly P; Reuhl, Kenneth R; Mainelis, Gediminas; Minko, Tamara
Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance Journal Article
In: Proc Natl Acad Sci U S A, vol. 107, no. 23, pp. 10737–10742, 2010, ISSN: 1091-6490.
@article{pmid20498076,
title = {Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance},
author = {Olga B Garbuzenko and Maha Saad and Vitaly P Pozharov and Kenneth R Reuhl and Gediminas Mainelis and Tamara Minko},
doi = {10.1073/pnas.1004604107},
issn = {1091-6490},
year = {2010},
date = {2010-06-01},
journal = {Proc Natl Acad Sci U S A},
volume = {107},
number = {23},
pages = {10737--10742},
abstract = {Development of cancer cell resistance, low accumulation of therapeutic drug in the lungs, and severe adverse treatment side effects represent main obstacles to efficient chemotherapy of lung cancer. To overcome these difficulties, we propose inhalation local delivery of anticancer drugs in combination with suppressors of pump and nonpump cellular resistance. To test this approach, nanoscale-based delivery systems containing doxorubicin as a cell death inducer, antisense oligonucleotides targeted to MRP1 mRNA as a suppressor of pump resistance and to BCL2 mRNA as a suppressor of nonpump resistance, were developed and examined on an orthotopic murine model of human lung carcinoma. The experimental results show high antitumor activity and low adverse side effects of proposed complex inhalatory treatment that cannot be achieved by individual components applied separately. The present work potentially contributes to the treatment of lung cancer by describing a unique combinatorial local inhalation delivery of drugs and suppressors of pump and nonpump cellular resistance.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Development of cancer cell resistance, low accumulation of therapeutic drug in the lungs, and severe adverse treatment side effects represent main obstacles to efficient chemotherapy of lung cancer. To overcome these difficulties, we propose inhalation local delivery of anticancer drugs in combination with suppressors of pump and nonpump cellular resistance. To test this approach, nanoscale-based delivery systems containing doxorubicin as a cell death inducer, antisense oligonucleotides targeted to MRP1 mRNA as a suppressor of pump resistance and to BCL2 mRNA as a suppressor of nonpump resistance, were developed and examined on an orthotopic murine model of human lung carcinoma. The experimental results show high antitumor activity and low adverse side effects of proposed complex inhalatory treatment that cannot be achieved by individual components applied separately. The present work potentially contributes to the treatment of lung cancer by describing a unique combinatorial local inhalation delivery of drugs and suppressors of pump and nonpump cellular resistance.
Zhao, Xin; Ren, Guangwen; Liang, Li; Ai, Phillip Z; Zheng, Betty; Tischfield, Jay A; Shi, Yufang; Shao, Changshun
Brief report: interferon-gamma induces expansion of Lin(-)Sca-1(+)C-Kit(+) Cells Journal Article
In: Stem Cells, vol. 28, no. 1, pp. 122–126, 2010, ISSN: 1549-4918.
@article{pmid19890981,
title = {Brief report: interferon-gamma induces expansion of Lin(-)Sca-1(+)C-Kit(+) Cells},
author = {Xin Zhao and Guangwen Ren and Li Liang and Phillip Z Ai and Betty Zheng and Jay A Tischfield and Yufang Shi and Changshun Shao},
doi = {10.1002/stem.252},
issn = {1549-4918},
year = {2010},
date = {2010-01-01},
journal = {Stem Cells},
volume = {28},
number = {1},
pages = {122--126},
abstract = {The balance between Th1 and Th2 cells is critical for homeostasis of the immune system. Th1 cells can also regulate hematopoietic progenitor cell homeostasis by production of oncostatin M. Here we show that Th1 cell products, but not those of Th2 cells, caused a rapid expansion of lineage(-)Sca-1(+)C-kit(+) (LSK) cells in vivo and in vitro. Among Th1 cytokines, interferon-gamma (IFNgamma) was found to play a major role in this expansion by activating the expression of Sca-1 in lineage(-)Sca-1(-)C-kit(+) cells. This process was dependent on IFNgammaR1 signaling and the STAT1 pathway. Furthermore, those IFNgamma-induced LSK cells had a higher proliferation potential than control LSK cells. In addition, while the overall production of colony-forming units in bone marrow was decreased after IFNgamma treatment, the sorted LSK cells could give rise to a higher yield of colony-forming units. Finally, the IFNgamma-induced hematopoiesis was biased toward the differentiation of myeloid lineages. Therefore, our findings demonstrated a novel role of IFNgamma in activating hematopoietic progenitor cells and provide a new insight into the clinical application of interferon.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The balance between Th1 and Th2 cells is critical for homeostasis of the immune system. Th1 cells can also regulate hematopoietic progenitor cell homeostasis by production of oncostatin M. Here we show that Th1 cell products, but not those of Th2 cells, caused a rapid expansion of lineage(-)Sca-1(+)C-kit(+) (LSK) cells in vivo and in vitro. Among Th1 cytokines, interferon-gamma (IFNgamma) was found to play a major role in this expansion by activating the expression of Sca-1 in lineage(-)Sca-1(-)C-kit(+) cells. This process was dependent on IFNgammaR1 signaling and the STAT1 pathway. Furthermore, those IFNgamma-induced LSK cells had a higher proliferation potential than control LSK cells. In addition, while the overall production of colony-forming units in bone marrow was decreased after IFNgamma treatment, the sorted LSK cells could give rise to a higher yield of colony-forming units. Finally, the IFNgamma-induced hematopoiesis was biased toward the differentiation of myeloid lineages. Therefore, our findings demonstrated a novel role of IFNgamma in activating hematopoietic progenitor cells and provide a new insight into the clinical application of interferon.
2009
Bayraktar, Mehmet; Peltier, Morgan; Vetrano, Anna; Arita, Yuko; Gurzenda, Ellen; Joseph, Ansamma; Kazzaz, Jeffrey; Sharma, Surendra; Hanna, Nazeeh
IL-10 modulates placental responses to TLR ligands Journal Article
In: Am J Reprod Immunol, vol. 62, no. 6, pp. 390–399, 2009, ISSN: 1600-0897.
@article{pmid19821803,
title = {IL-10 modulates placental responses to TLR ligands},
author = {Mehmet Bayraktar and Morgan Peltier and Anna Vetrano and Yuko Arita and Ellen Gurzenda and Ansamma Joseph and Jeffrey Kazzaz and Surendra Sharma and Nazeeh Hanna},
doi = {10.1111/j.1600-0897.2009.00756.x},
issn = {1600-0897},
year = {2009},
date = {2009-12-01},
journal = {Am J Reprod Immunol},
volume = {62},
number = {6},
pages = {390--399},
abstract = {PROBLEM: Intra-uterine infections increase production of pro-inflammatory cytokines. It is unclear whether different infectious agents determine the relative expression of pro-and anti-inflammatory cytokines.
METHODS OF STUDY: We compared the placental inflammatory response induced by bacterial lipopolysaccharide (LPS, endotoxin from Gram-negative bacteria) with those induced by lipoteichoic acid (LTA, a cell wall component of Gram-positive bacteria). Placental explants from term delivery were treated with either LPS or LTA, in the presence or absence of IL-10, for 24 hrs. Cytokines, prostaglandin E(2) (PGE(2)) production and cyclo-oxygenase-2 (COX-2) expression were quantified.
RESULTS: Both LTA and LPS significantly induced several cytokines with LPS eliciting more potent effects. IL-6 and IL-8 were induced to comparable levels in response to both LTA and LPS whereas monocyte chemotactic protein-1 (MCP-1) production was induced more by LTA, demonstrating a differential placental response to a specific toll-like receptor (TLR) ligand. IL-10 treatment significantly reduced most pro-inflammatory cytokines as well as PGE(2) induced by both LPS and LTA. Interestingly, IL-10 down-regulated LTA-mediated MCP1 induction, but not that mediated by LPS. Moreover, IL-10 was more effective in down-regulating PGE(2) after LPS- when compared with LTA stimulation.
CONCLUSIONS: Our results demonstrate that placental exposure to LTA and LPS appear to trigger distinct cytokine responses that can be modulated by IL-10.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
PROBLEM: Intra-uterine infections increase production of pro-inflammatory cytokines. It is unclear whether different infectious agents determine the relative expression of pro-and anti-inflammatory cytokines.
METHODS OF STUDY: We compared the placental inflammatory response induced by bacterial lipopolysaccharide (LPS, endotoxin from Gram-negative bacteria) with those induced by lipoteichoic acid (LTA, a cell wall component of Gram-positive bacteria). Placental explants from term delivery were treated with either LPS or LTA, in the presence or absence of IL-10, for 24 hrs. Cytokines, prostaglandin E(2) (PGE(2)) production and cyclo-oxygenase-2 (COX-2) expression were quantified.
RESULTS: Both LTA and LPS significantly induced several cytokines with LPS eliciting more potent effects. IL-6 and IL-8 were induced to comparable levels in response to both LTA and LPS whereas monocyte chemotactic protein-1 (MCP-1) production was induced more by LTA, demonstrating a differential placental response to a specific toll-like receptor (TLR) ligand. IL-10 treatment significantly reduced most pro-inflammatory cytokines as well as PGE(2) induced by both LPS and LTA. Interestingly, IL-10 down-regulated LTA-mediated MCP1 induction, but not that mediated by LPS. Moreover, IL-10 was more effective in down-regulating PGE(2) after LPS- when compared with LTA stimulation.
CONCLUSIONS: Our results demonstrate that placental exposure to LTA and LPS appear to trigger distinct cytokine responses that can be modulated by IL-10.
METHODS OF STUDY: We compared the placental inflammatory response induced by bacterial lipopolysaccharide (LPS, endotoxin from Gram-negative bacteria) with those induced by lipoteichoic acid (LTA, a cell wall component of Gram-positive bacteria). Placental explants from term delivery were treated with either LPS or LTA, in the presence or absence of IL-10, for 24 hrs. Cytokines, prostaglandin E(2) (PGE(2)) production and cyclo-oxygenase-2 (COX-2) expression were quantified.
RESULTS: Both LTA and LPS significantly induced several cytokines with LPS eliciting more potent effects. IL-6 and IL-8 were induced to comparable levels in response to both LTA and LPS whereas monocyte chemotactic protein-1 (MCP-1) production was induced more by LTA, demonstrating a differential placental response to a specific toll-like receptor (TLR) ligand. IL-10 treatment significantly reduced most pro-inflammatory cytokines as well as PGE(2) induced by both LPS and LTA. Interestingly, IL-10 down-regulated LTA-mediated MCP1 induction, but not that mediated by LPS. Moreover, IL-10 was more effective in down-regulating PGE(2) after LPS- when compared with LTA stimulation.
CONCLUSIONS: Our results demonstrate that placental exposure to LTA and LPS appear to trigger distinct cytokine responses that can be modulated by IL-10.
Jin, Feng; Fondell, Joseph D
A novel androgen receptor-binding element modulates Cdc6 transcription in prostate cancer cells during cell-cycle progression Journal Article
In: Nucleic Acids Res, vol. 37, no. 14, pp. 4826–4838, 2009, ISSN: 1362-4962.
@article{pmid19520769,
title = {A novel androgen receptor-binding element modulates Cdc6 transcription in prostate cancer cells during cell-cycle progression},
author = {Feng Jin and Joseph D Fondell},
doi = {10.1093/nar/gkp510},
issn = {1362-4962},
year = {2009},
date = {2009-08-01},
journal = {Nucleic Acids Res},
volume = {37},
number = {14},
pages = {4826--4838},
abstract = {The androgen receptor (AR) plays a pivotal role in the onset and progression of prostate cancer by promoting cellular proliferation. Recent studies suggest AR is a master regulator of G1-S progression and possibly a licensing factor for DNA replication yet the mechanisms remain poorly defined. Here we report that AR targets the human Cdc6 gene for transcriptional regulation. Cdc6 is an essential regulator of DNA replication in eukaryotic cells and its mRNA expression is inversely modulated by androgen or antiandrogen treatment in androgen-sensitive prostate cancer cells. AR binds at a distinct androgen-response element (ARE) in the Cdc6 promoter that is functionally required for androgen-dependent Cdc6 transcription. We found that peak AR occupancy at the novel ARE occurs during the G1/S phase concomitant with peak Cdc6 mRNA expression. We also identified several of the coactivators and corepressors involved in AR-dependent Cdc6 transcriptional regulation in vivo and further characterized ligand-induced alterations in histone acetylation and methylation at the Cdc6 promoter. Significantly, AR silencing in prostate cancer cells markedly decreases Cdc6 expression and androgen-dependent cellular proliferation. Collectively, our results suggest that Cdc6 is a key regulatory target for AR and provide new insights into the mechanisms of prostate cancer cell proliferation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The androgen receptor (AR) plays a pivotal role in the onset and progression of prostate cancer by promoting cellular proliferation. Recent studies suggest AR is a master regulator of G1-S progression and possibly a licensing factor for DNA replication yet the mechanisms remain poorly defined. Here we report that AR targets the human Cdc6 gene for transcriptional regulation. Cdc6 is an essential regulator of DNA replication in eukaryotic cells and its mRNA expression is inversely modulated by androgen or antiandrogen treatment in androgen-sensitive prostate cancer cells. AR binds at a distinct androgen-response element (ARE) in the Cdc6 promoter that is functionally required for androgen-dependent Cdc6 transcription. We found that peak AR occupancy at the novel ARE occurs during the G1/S phase concomitant with peak Cdc6 mRNA expression. We also identified several of the coactivators and corepressors involved in AR-dependent Cdc6 transcriptional regulation in vivo and further characterized ligand-induced alterations in histone acetylation and methylation at the Cdc6 promoter. Significantly, AR silencing in prostate cancer cells markedly decreases Cdc6 expression and androgen-dependent cellular proliferation. Collectively, our results suggest that Cdc6 is a key regulatory target for AR and provide new insights into the mechanisms of prostate cancer cell proliferation.
Mathew, Robin; Karp, Cristina M; Beaudoin, Brian; Vuong, Nhan; Chen, Guanghua; Chen, Hsin-Yi; Bray, Kevin; Reddy, Anupama; Bhanot, Gyan; Gelinas, Celine; Dipaola, Robert S; Karantza-Wadsworth, Vassiliki; White, Eileen
Autophagy suppresses tumorigenesis through elimination of p62 Journal Article
In: Cell, vol. 137, no. 6, pp. 1062–1075, 2009, ISSN: 1097-4172.
@article{pmid19524509,
title = {Autophagy suppresses tumorigenesis through elimination of p62},
author = {Robin Mathew and Cristina M Karp and Brian Beaudoin and Nhan Vuong and Guanghua Chen and Hsin-Yi Chen and Kevin Bray and Anupama Reddy and Gyan Bhanot and Celine Gelinas and Robert S Dipaola and Vassiliki Karantza-Wadsworth and Eileen White},
doi = {10.1016/j.cell.2009.03.048},
issn = {1097-4172},
year = {2009},
date = {2009-06-01},
journal = {Cell},
volume = {137},
number = {6},
pages = {1062--1075},
abstract = {Allelic loss of the essential autophagy gene beclin1 occurs in human cancers and renders mice tumor-prone suggesting that autophagy is a tumor-suppression mechanism. While tumor cells utilize autophagy to survive metabolic stress, autophagy also mitigates the resulting cellular damage that may limit tumorigenesis. In response to stress, autophagy-defective tumor cells preferentially accumulated p62/SQSTM1 (p62), endoplasmic reticulum (ER) chaperones, damaged mitochondria, reactive oxygen species (ROS), and genome damage. Moreover, suppressing ROS or p62 accumulation prevented damage resulting from autophagy defects indicating that failure to regulate p62 caused oxidative stress. Importantly, sustained p62 expression resulting from autophagy defects was sufficient to alter NF-kappaB regulation and gene expression and to promote tumorigenesis. Thus, defective autophagy is a mechanism for p62 upregulation commonly observed in human tumors that contributes directly to tumorigenesis likely by perturbing the signal transduction adaptor function of p62-controlling pathways critical for oncogenesis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Allelic loss of the essential autophagy gene beclin1 occurs in human cancers and renders mice tumor-prone suggesting that autophagy is a tumor-suppression mechanism. While tumor cells utilize autophagy to survive metabolic stress, autophagy also mitigates the resulting cellular damage that may limit tumorigenesis. In response to stress, autophagy-defective tumor cells preferentially accumulated p62/SQSTM1 (p62), endoplasmic reticulum (ER) chaperones, damaged mitochondria, reactive oxygen species (ROS), and genome damage. Moreover, suppressing ROS or p62 accumulation prevented damage resulting from autophagy defects indicating that failure to regulate p62 caused oxidative stress. Importantly, sustained p62 expression resulting from autophagy defects was sufficient to alter NF-kappaB regulation and gene expression and to promote tumorigenesis. Thus, defective autophagy is a mechanism for p62 upregulation commonly observed in human tumors that contributes directly to tumorigenesis likely by perturbing the signal transduction adaptor function of p62-controlling pathways critical for oncogenesis.
Postel, Edith H; Wohlman, Irene; Zou, Xiaoming; Juan, Todd; Sun, Ning; D'Agostin, Diane; Cuellar, Maria; Choi, Theresa; Notterman, Daniel A; Perle, Krista M D La
Targeted deletion of Nm23/nucleoside diphosphate kinase A and B reveals their requirement for definitive erythropoiesis in the mouse embryo Journal Article
In: Dev Dyn, vol. 238, no. 3, pp. 775–787, 2009, ISSN: 1058-8388.
@article{pmid19235734,
title = {Targeted deletion of Nm23/nucleoside diphosphate kinase A and B reveals their requirement for definitive erythropoiesis in the mouse embryo},
author = {Edith H Postel and Irene Wohlman and Xiaoming Zou and Todd Juan and Ning Sun and Diane D'Agostin and Maria Cuellar and Theresa Choi and Daniel A Notterman and Krista M D La Perle},
doi = {10.1002/dvdy.21887},
issn = {1058-8388},
year = {2009},
date = {2009-03-01},
journal = {Dev Dyn},
volume = {238},
number = {3},
pages = {775--787},
abstract = {The ubiquitously expressed nucleoside diphosphate kinases (Nm23/NDPK/Awd) are a large family of multifunctional enzymes implicated in nucleic acid metabolism and in normal and abnormal development. Here, we describe the generation and characterization of NDPK A- and B-deficient (Nme1(-/-)/Nme2(-/-)) mice in which >95% of the enzyme activity is eliminated. These mice are undersized, die perinatally, and exhibit a spectrum of hematological phenotypes including severe anemia, impaired maturation of erythrocytes, and abnormal hematopoiesis in the liver and bone marrow. Flow cytometric analysis of developing Nme1(-/-)/Nme2(-/-) erythroid cells indicated that the major iron transport receptor molecule TfR1 is attenuated concomitant with a reduction of intracellular iron, suggesting that TfR1 is a downstream target of NDPKs and that reduced iron in Nme1(-/-)/Nme2(-/-) erythroblasts is inhibiting their development. We conclude that Nm23/NDPKs play critical roles in definitive erythroid development. Our novel mouse model also links erythropoiesis and nucleotide metabolism.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The ubiquitously expressed nucleoside diphosphate kinases (Nm23/NDPK/Awd) are a large family of multifunctional enzymes implicated in nucleic acid metabolism and in normal and abnormal development. Here, we describe the generation and characterization of NDPK A- and B-deficient (Nme1(-/-)/Nme2(-/-)) mice in which >95% of the enzyme activity is eliminated. These mice are undersized, die perinatally, and exhibit a spectrum of hematological phenotypes including severe anemia, impaired maturation of erythrocytes, and abnormal hematopoiesis in the liver and bone marrow. Flow cytometric analysis of developing Nme1(-/-)/Nme2(-/-) erythroid cells indicated that the major iron transport receptor molecule TfR1 is attenuated concomitant with a reduction of intracellular iron, suggesting that TfR1 is a downstream target of NDPKs and that reduced iron in Nme1(-/-)/Nme2(-/-) erythroblasts is inhibiting their development. We conclude that Nm23/NDPKs play critical roles in definitive erythroid development. Our novel mouse model also links erythropoiesis and nucleotide metabolism.
2008
Kawamura, Kazuyuki; Yao, Karen; Shukaliak-Quandt, Jacqueline A; Huh, Jaebong; Baig, Mirza; Quigley, Laura; Ito, Naoko; Necker, Antje; McFarland, Henry F; Muraro, Paolo A; Martin, Roland; Ito, Kouichi
Different development of myelin basic protein agonist- and antagonist-specific human TCR transgenic T cells in the thymus and periphery Journal Article
In: J Immunol, vol. 181, no. 8, pp. 5462–5472, 2008, ISSN: 1550-6606.
@article{pmid18832703,
title = {Different development of myelin basic protein agonist- and antagonist-specific human TCR transgenic T cells in the thymus and periphery},
author = {Kazuyuki Kawamura and Karen Yao and Jacqueline A Shukaliak-Quandt and Jaebong Huh and Mirza Baig and Laura Quigley and Naoko Ito and Antje Necker and Henry F McFarland and Paolo A Muraro and Roland Martin and Kouichi Ito},
doi = {10.4049/jimmunol.181.8.5462},
issn = {1550-6606},
year = {2008},
date = {2008-10-01},
journal = {J Immunol},
volume = {181},
number = {8},
pages = {5462--5472},
abstract = {Myelin basic protein (MBP)-specific T cells are thought to play a role in the development of multiple sclerosis. MBP residues 111-129 compose an immunodominant epitope cluster restricted by HLA-DRB1*0401. The sequence of residues 111-129 of MBP (MBP(111-129)) differs in humans (MBP122:Arg) and mice (MBP122:Lys) at aa 122. We previously found that approximately 50% of human MBP(111-129) (MBP122:Arg)-specific T cell clones, including MS2-3C8 can proliferate in response to mouse MBP(111-129) (MBP122:Lys). However, the other half of T cell clones, including HD4-1C2, cannot proliferate in response to MBP(111-129) (MBP122:Lys). We found that MBP(111-129) (MBP122:Lys) is an antagonist for HD4-1C2 TCR, therefore, MS2-3C8 and HD4-1C2 TCRs are agonist- and antagonist-specific TCRs in mice, respectively. Therefore, we examined the development of HD4-1C2 TCR and MS2-3C8 TCR transgenic (Tg) T cells in the thymus and periphery. We found that dual TCR expression exclusively facilitates the development of MBP(111-129) TCR Tg T cells in the periphery of HD4-1C2 TCR/HLA-DRB1*0401 Tg mice although it is not required for their development in the thymus. We also found that MS2-3C8 TCR Tg CD8(+) T cells develop along with MS2-3C8 TCR Tg CD4(+) T cells, and that dual TCR expression was crucial for the development of MS2-3C8 TCR Tg CD4(+) and CD8(+) T cells in the thymus and periphery, respectively. These results suggest that thymic and peripheral development of MBP-specific T cells are different; however, dual TCR expression can facilitate their development.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Myelin basic protein (MBP)-specific T cells are thought to play a role in the development of multiple sclerosis. MBP residues 111-129 compose an immunodominant epitope cluster restricted by HLA-DRB1*0401. The sequence of residues 111-129 of MBP (MBP(111-129)) differs in humans (MBP122:Arg) and mice (MBP122:Lys) at aa 122. We previously found that approximately 50% of human MBP(111-129) (MBP122:Arg)-specific T cell clones, including MS2-3C8 can proliferate in response to mouse MBP(111-129) (MBP122:Lys). However, the other half of T cell clones, including HD4-1C2, cannot proliferate in response to MBP(111-129) (MBP122:Lys). We found that MBP(111-129) (MBP122:Lys) is an antagonist for HD4-1C2 TCR, therefore, MS2-3C8 and HD4-1C2 TCRs are agonist- and antagonist-specific TCRs in mice, respectively. Therefore, we examined the development of HD4-1C2 TCR and MS2-3C8 TCR transgenic (Tg) T cells in the thymus and periphery. We found that dual TCR expression exclusively facilitates the development of MBP(111-129) TCR Tg T cells in the periphery of HD4-1C2 TCR/HLA-DRB1*0401 Tg mice although it is not required for their development in the thymus. We also found that MS2-3C8 TCR Tg CD8(+) T cells develop along with MS2-3C8 TCR Tg CD4(+) T cells, and that dual TCR expression was crucial for the development of MS2-3C8 TCR Tg CD4(+) and CD8(+) T cells in the thymus and periphery, respectively. These results suggest that thymic and peripheral development of MBP-specific T cells are different; however, dual TCR expression can facilitate their development.
Weinberger, Barry; Quizon, Cecile; Vetrano, Anna M; Archer, Faith; Laskin, Jeffrey D; Laskin, Debra L
Mechanisms mediating reduced responsiveness of neonatal neutrophils to lipoxin A4 Journal Article
In: Pediatr Res, vol. 64, no. 4, pp. 393–398, 2008, ISSN: 1530-0447.
@article{pmid18535486,
title = {Mechanisms mediating reduced responsiveness of neonatal neutrophils to lipoxin A4},
author = {Barry Weinberger and Cecile Quizon and Anna M Vetrano and Faith Archer and Jeffrey D Laskin and Debra L Laskin},
doi = {10.1203/PDR.0b013e318180e4af},
issn = {1530-0447},
year = {2008},
date = {2008-10-01},
journal = {Pediatr Res},
volume = {64},
number = {4},
pages = {393--398},
abstract = {Lipoxin A4 is an eicosanoid that plays a key role in the resolution of neutrophilic inflammation. In these studies, we investigated the hypothesis that responses to lipoxin A4 are impaired in neonates, relative to adults. Lipoxin A4 was found to inhibit chemotaxis and respiratory burst in adult neutrophils. In contrast, it had no effect on these activities in neonatal neutrophils. In addition, while lipoxin A4 augmented apoptosis in LPS-treated adult neutrophils, apoptosis in neonatal cells was not affected by lipoxin A4 alone or in combination with LPS. The biologic actions of anti-inflammatory eicosanoids are mediated, in part, via the transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Expression of PPAR-gamma mRNA and its target gene, neutrophil gelatinase-associated lipocalin (NGAL), were significantly reduced in neonatal cells when compared with adult cells. Moreover, whereas treatment of adult neutrophils with lipoxin A4 increased PPAR-gamma expression, no effects were observed in neonatal cells. 5- and 15-lipoxygenase, enzymes required for the synthesis of lipoxin A4, were also reduced in neonatal neutrophils. These findings suggest that the anti-inflammatory activity of lipoxin A4 is impaired in neonatal neutrophils and that this is due, in part, to reduced PPAR-gamma signaling. This may contribute to diseases associated with chronic inflammation in neonates.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Lipoxin A4 is an eicosanoid that plays a key role in the resolution of neutrophilic inflammation. In these studies, we investigated the hypothesis that responses to lipoxin A4 are impaired in neonates, relative to adults. Lipoxin A4 was found to inhibit chemotaxis and respiratory burst in adult neutrophils. In contrast, it had no effect on these activities in neonatal neutrophils. In addition, while lipoxin A4 augmented apoptosis in LPS-treated adult neutrophils, apoptosis in neonatal cells was not affected by lipoxin A4 alone or in combination with LPS. The biologic actions of anti-inflammatory eicosanoids are mediated, in part, via the transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Expression of PPAR-gamma mRNA and its target gene, neutrophil gelatinase-associated lipocalin (NGAL), were significantly reduced in neonatal cells when compared with adult cells. Moreover, whereas treatment of adult neutrophils with lipoxin A4 increased PPAR-gamma expression, no effects were observed in neonatal cells. 5- and 15-lipoxygenase, enzymes required for the synthesis of lipoxin A4, were also reduced in neonatal neutrophils. These findings suggest that the anti-inflammatory activity of lipoxin A4 is impaired in neonatal neutrophils and that this is due, in part, to reduced PPAR-gamma signaling. This may contribute to diseases associated with chronic inflammation in neonates.
2007
Mathew, Robin; Kongara, Sameera; Beaudoin, Brian; Karp, Cristina M; Bray, Kevin; Degenhardt, Kurt; Chen, Guanghua; Jin, Shengkan; White, Eileen
Autophagy suppresses tumor progression by limiting chromosomal instability Journal Article
In: Genes Dev, vol. 21, no. 11, pp. 1367–1381, 2007, ISSN: 0890-9369.
@article{pmid17510285,
title = {Autophagy suppresses tumor progression by limiting chromosomal instability},
author = {Robin Mathew and Sameera Kongara and Brian Beaudoin and Cristina M Karp and Kevin Bray and Kurt Degenhardt and Guanghua Chen and Shengkan Jin and Eileen White},
doi = {10.1101/gad.1545107},
issn = {0890-9369},
year = {2007},
date = {2007-06-01},
journal = {Genes Dev},
volume = {21},
number = {11},
pages = {1367--1381},
abstract = {Autophagy is a bulk degradation process that promotes survival under metabolic stress, but it can also be a means of cell death if executed to completion. Monoallelic loss of the essential autophagy gene beclin1 causes susceptibility to metabolic stress, but also promotes tumorigenesis. This raises the paradox that the loss of a survival pathway enhances tumor growth, where the exact mechanism is not known. Here, we show that compromised autophagy promoted chromosome instability. Failure to sustain metabolism through autophagy was associated with increased DNA damage, gene amplification, and aneuploidy, and this genomic instability may promote tumorigenesis. Thus, autophagy maintains metabolism and survival during metabolic stress that serves to protect the genome, providing an explanation for how the loss of a survival pathway leads to tumor progression. Identification of this novel role of autophagy may be important for rational chemotherapy and therapeutic exploitation of autophagy inducers as potential chemopreventive agents.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Autophagy is a bulk degradation process that promotes survival under metabolic stress, but it can also be a means of cell death if executed to completion. Monoallelic loss of the essential autophagy gene beclin1 causes susceptibility to metabolic stress, but also promotes tumorigenesis. This raises the paradox that the loss of a survival pathway enhances tumor growth, where the exact mechanism is not known. Here, we show that compromised autophagy promoted chromosome instability. Failure to sustain metabolism through autophagy was associated with increased DNA damage, gene amplification, and aneuploidy, and this genomic instability may promote tumorigenesis. Thus, autophagy maintains metabolism and survival during metabolic stress that serves to protect the genome, providing an explanation for how the loss of a survival pathway leads to tumor progression. Identification of this novel role of autophagy may be important for rational chemotherapy and therapeutic exploitation of autophagy inducers as potential chemopreventive agents.
Weinberger, Barry; Vetrano, Anna M; Syed, Kirin; Murthy, Sowmya; Hanna, Nazeeh; Laskin, Jeffrey D; Laskin, Debra L
Influence of labor on neonatal neutrophil apoptosis, and inflammatory activity Journal Article
In: Pediatr Res, vol. 61, no. 5 Pt 1, pp. 572–577, 2007, ISSN: 0031-3998.
@article{pmid17413861,
title = {Influence of labor on neonatal neutrophil apoptosis, and inflammatory activity},
author = {Barry Weinberger and Anna M Vetrano and Kirin Syed and Sowmya Murthy and Nazeeh Hanna and Jeffrey D Laskin and Debra L Laskin},
doi = {10.1203/pdr.0b013e318045be38},
issn = {0031-3998},
year = {2007},
date = {2007-05-01},
journal = {Pediatr Res},
volume = {61},
number = {5 Pt 1},
pages = {572--577},
abstract = {Neutrophil apoptosis is impaired in neonates, and this contributes to prolonged inflammation and tissue injury in infants after infection or trauma. In the present studies, we investigated whether labor generates mediators that further suppress apoptosis. We found that neutrophil apoptosis was reduced in neonates exposed to labor, when compared with infants delivered by cesarean section before labor. This was not due to alterations in caspase-3 or inhibitor of apoptosis protein-2 (IAP-2). In contrast, labor primed neutrophils to express tumor necrosis factor alpha (TNF-alpha), suggesting that proinflammatory mediators contribute to reduced apoptosis after labor. Eicosanoids generated via cyclooxygenase-2 (Cox-2) and lipoxygenase (Lox) also regulate neutrophil apoptosis. 15-Lox, which generates proapoptotic lipoxins, but not Cox-2, was greater in neutrophils before labor, relative to cells exposed to labor. Anti-inflammatory eicosanoids exert their effects in part via peroxisome proliferator-activated receptor gamma (PPAR-gamma). Expression of gelatinase-associated lipocalin and catalase, two markers of PPAR-gamma activity, were increased in neonatal neutrophils before labor, relative to cells exposed to labor. These findings suggest that the anti-inflammatory environment is maintained before labor, in part, by eicosanoids. Although increased neutrophil longevity after labor is important for host defense in the immediate newborn period, it may contribute to inflammatory or oxidative injury in susceptible infants.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Neutrophil apoptosis is impaired in neonates, and this contributes to prolonged inflammation and tissue injury in infants after infection or trauma. In the present studies, we investigated whether labor generates mediators that further suppress apoptosis. We found that neutrophil apoptosis was reduced in neonates exposed to labor, when compared with infants delivered by cesarean section before labor. This was not due to alterations in caspase-3 or inhibitor of apoptosis protein-2 (IAP-2). In contrast, labor primed neutrophils to express tumor necrosis factor alpha (TNF-alpha), suggesting that proinflammatory mediators contribute to reduced apoptosis after labor. Eicosanoids generated via cyclooxygenase-2 (Cox-2) and lipoxygenase (Lox) also regulate neutrophil apoptosis. 15-Lox, which generates proapoptotic lipoxins, but not Cox-2, was greater in neutrophils before labor, relative to cells exposed to labor. Anti-inflammatory eicosanoids exert their effects in part via peroxisome proliferator-activated receptor gamma (PPAR-gamma). Expression of gelatinase-associated lipocalin and catalase, two markers of PPAR-gamma activity, were increased in neonatal neutrophils before labor, relative to cells exposed to labor. These findings suggest that the anti-inflammatory environment is maintained before labor, in part, by eicosanoids. Although increased neutrophil longevity after labor is important for host defense in the immediate newborn period, it may contribute to inflammatory or oxidative injury in susceptible infants.