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1.  Systemic inflammation associated with mechanical ventilation among extremely preterm infants 
Cytokine  2012;61(1):315-322.
Little evidence is available to document that mechanical ventilation is an antecedent of systemic inflammation in preterm humans. We obtained blood on postnatal day 14 from 726 infants born before the 28th week of gestation and measured the concentrations of 25 inflammation-related proteins. We created multivariable models to assess the relationship between duration of ventilation and protein concentrations in the top quartile. Compared to newborns ventilated for fewer than 7 days (N=247), those ventilated for 14 days (N=330) were more likely to have elevated blood concentrations of pro-inflammatory cytokines (IL-1β, TNF-α), chemokines (IL-8, MCP-1), an adhesion molecule (ICAM-1), and a matrix metalloprotease (MMP-9), and less likely to have elevated blood concentrations of two chemokines (RANTES, MIP-1β), a matrix metalloproteinase (MMP-1), and a growth factor (VEGF). Newborns ventilated for 7-13 days (N=149) had systemic inflammation that approximated the pattern of newborns ventilated for 14 days. These relationships were not confounded by chorioamnionitis or antenatal corticosteroid exposure, and were not altered appreciably among infants with and without bacteremia. These findings suggest that two weeks of ventilation are more likely than shorter durations of ventilation to be accompanied by high blood concentrations of pro-inflammatory proteins indicative of systemic inflammation, and by low concentrations of proteins that might protect from inflammation-mediated organ injury.
PMCID: PMC3518391  PMID: 23148992
inflammation; ventilation; preterm infant; cytokine; chemokine
2.  Neonatal cytokines and chemokines and risk of Autism Spectrum Disorder: the Early Markers for Autism (EMA) study: a case-control study 
Biologic markers of infection and inflammation have been associated with Autism Spectrum Disorders (ASD) but prior studies have largely relied on specimens taken after clinical diagnosis. Research on potential biologic markers early in neurodevelopment is required to evaluate possible causal pathways and screening profiles.
To investigate levels of cytokines and chemokines in newborn blood specimens as possible early biologic markers for autism.
We conducted a population-based case-control study nested within the cohort of infants born from July 2000 to September 2001 to women who participated in the prenatal screening program in Orange County, California, USA. The study population included children ascertained from the California Department of Developmental Services with Autism Spectrum Disorder (ASD, n = 84), or developmental delay but not ASD (DD, n = 49), and general population controls randomly sampled from the birth certificate files and frequency matched to ASD cases on sex, birth month and birth year (GP, n = 159). Cytokine and chemokine concentrations were measured in archived neonatal blood specimens collected for routine newborn screening.
Cytokines were not detected in the vast majority of newborn samples regardless of case or control status. However, the chemokine monocyte chemotactic protein-1 (MCP-1) was elevated and the chemokine Regulated upon Activation Normal T-Cell Expressed and Secreted (RANTES) was decreased in ASD cases compared to GP controls. The chemokines macrophage inflammatory protein-1alpha (MIP-1α) and RANTES were decreased in children with DD compared to GP controls.
Measurement of immune system function in the first few days of life may aid in the early identification of abnormal neurodevelopment and shed light on the biologic mechanisms underlying normal neurodevelopment.
PMCID: PMC4080514  PMID: 24951035
Newborn; Cytokines; Chemokines; Autism spectrum disorders
3.  PPARα downregulates airway inflammation induced by lipopolysaccharide in the mouse 
Respiratory Research  2005;6(1):91.
Inflammation is a hallmark of acute lung injury and chronic airway diseases. In chronic airway diseases, it is associated with profound tissue remodeling. Peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor, that belongs to the nuclear receptor family. Agonists for PPARα have been recently shown to reduce lipopolysaccharide (LPS)- and cytokine-induced secretion of matrix metalloproteinase-9 (MMP-9) in human monocytes and rat mesangial cells, suggesting that PPARα may play a beneficial role in inflammation and tissue remodeling.
We have investigated the role of PPARα in a mouse model of LPS-induced airway inflammation characterized by neutrophil and macrophage infiltration, by production of the chemoattractants, tumor necrosis factor-α (TNF-α), keratinocyte derived-chemokine (KC), macrophage inflammatory protein-2 (MIP-2) and monocyte chemoattractant protein-1 (MCP-1), and by increased MMP-2 and MMP-9 activity in bronchoalveolar lavage fluid (BALF). The role of PPARα in this model was studied using both PPARα-deficient mice and mice treated with the PPARα activator, fenofibrate.
Upon intranasal exposure to LPS, PPARα-/- mice exhibited greater neutrophil and macrophage number in BALF, as well as increased levels of TNF-α, KC, MIP-2 and MCP-1, when compared to PPARα+/+ mice. PPARα-/- mice also displayed enhanced MMP-9 activity. Conversely, fenofibrate (0.15 to 15 mg/day) dose-dependently reduced the increase in neutrophil and macrophage number induced by LPS in wild-type mice. In animals treated with 15 mg/day fenofibrate, this effect was associated with a reduction in TNF-α, KC, MIP-2 and MCP-1 levels, as well as in MMP-2 and MMP-9 activity. PPARα-/- mice treated with 15 mg/day fenofibrate failed to exhibit decreased airway inflammatory cell infiltrate, demonstrating that PPARα mediates the anti-inflammatory effect of fenofibrate.
Using both genetic and pharmacological approaches, our data clearly show that PPARα downregulates cell infiltration, chemoattractant production and enhanced MMP activity triggered by LPS in mouse lung. This suggests that PPARα activation may have a beneficial effect in acute or chronic inflammatory airway disorders involving neutrophils and macrophages.
PMCID: PMC1199625  PMID: 16091136
PPARα; lipopolysaccharide; inflammation; neutrophil; macrophage; matrix metalloproteinase; mouse
4.  Vibrio vulnificus MO6-24/O Lipopolysaccharide Stimulates Superoxide Anion, Thromboxane B2, Matrix Metalloproteinase-9, Cytokine and Chemokine Release by Rat Brain Microglia in Vitro 
Marine Drugs  2014;12(4):1732-1756.
Although human exposure to Gram-negative Vibrio vulnificus (V. vulnificus) lipopolysaccharide (LPS) has been reported to result in septic shock, its impact on the central nervous system’s innate immunity remains undetermined. The purpose of this study was to determine whether V. vulnificus MO6-24/O LPS might activate rat microglia in vitro and stimulate the release of superoxide anion (O2−), a reactive oxygen species known to cause oxidative stress and neuronal injury in vivo. Brain microglia were isolated from neonatal rats, and then treated with either V. vulnificus MO6-24/O LPS or Escherichia coli O26:B6 LPS for 17 hours in vitro. O2− was determined by cytochrome C reduction, and matrix metalloproteinase-2 (MMP-2) and MMP-9 by gelatinase zymography. Generation of cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 alpha (IL-1α), IL-6, and transforming growth factor-beta 1 (TGF-β1), chemokines macrophage inflammatory protein (MIP-1α)/chemokine (C-C motif) ligand 3 (CCL3), MIP-2/chemokine (C-X-C motif) ligand 2 (CXCL2), monocyte chemotactic protein-1 (MCP-1)/CCL2, and cytokine-induced neutrophil chemoattractant-2alpha/beta (CINC-2α/β)/CXCL3, and brain-derived neurotrophic factor (BDNF), were determined by specific immunoassays. Priming of rat microglia by V. vulnificus MO6-24/O LPS in vitro yielded a bell-shaped dose-response curve for PMA (phorbol 12-myristate 13-acetate)-stimulated O2− generation: (1) 0.1–1 ng/mL V. vulnificus LPS enhanced O2− generation significantly but with limited inflammatory mediator generation; (2) 10–100 ng/mL V. vulnificus LPS maximized O2− generation with concomitant release of thromboxane B2 (TXB2), matrix metalloproteinase-9 (MMP-9), and several cytokines and chemokines; (3) 1000–100,000 ng/mL V. vulnificus LPS, with the exception of TXB2, yielded both attenuated O2− production, and a progressive decrease in MMP-9, cytokines and chemokines investigated. Thus concentration-dependent treatment of neonatal brain microglia with V. vulnificus MO6-24/O LPS resulted in a significant rise in O2− production, followed by a progressive decrease in O2− release, with concomitant release of lactic dehydrogenase (LDH), and generation of TXB2, MMP-9, cytokines and chemokines. We hypothesize that the inflammatory mediators investigated may be cytotoxic to microglia in vitro, by an as yet undetermined autocrine mechanism. Although V. vulnificus LPS was less potent than E. coli LPS in vitro, inflammatory mediator release by the former was clearly more efficacious. Finally, we hypothesize that should V. vulnificus LPS gain entry into the CNS, it would be possible that microglia might become activated, resulting in high levels of O2− as well as neuroinflammatory TXB2, MMP-9, cytokines and chemokines.
PMCID: PMC4012467  PMID: 24675728
LPS; Escherichia coli; Vibrio vulnificus; rat microglia; cytokine; chemokine; superoxide; thromboxane; metalloproteinase; neuroinflammation; MMP-9
5.  The relationship between neonatal blood protein profiles and placenta histologic characteristics in extremely low gestation age newborns 
Pediatric research  2011;69(1):68-73.
Amniotic fluid infection with chorioamnionitis is associated with increased risks of morbidity and mortality in children born prematurely. These risks depend on the presence of a fetal inflammatory response. We measured the concentrations of 25 proteins in the blood of 871 infants born before the 28th week of gestation, and examined their placentas for acute inflammation. Newborns who had inflammatory lesions of the placenta were much more likely than their peers (p<0.01) to have elevated blood concentrations of cytokines (IL-1β, IL-6, TNF-alpha), chemokines (IL-8, MIP-1β, RANTES, I-TAC), adhesion molecules (ICAM-1, ICAM-3, E-selectin), matrix metalloproteinases (MMP1, MMP -9), the angiogenic inflammatory factor VEGF and its receptor VEGF-R2 as well as acute phase proteins (SAA and CRP) during first three days after birth. In contrast, newborns with poor placental perfusion had lower levels of inflammatory proteins (p<0.01, IL-6, RANTES, ICAM-1, ICAM-3, VCAM-1, E-selectin, MMP-1, MMP-9, MPO, VEGF). An inverse pattern was found between newborn levels of VEGF and its competitive inhibitor VEGF-R1 in both the inflamed and poorly perfused placenta categories. These results confirm the predictive value of placental histology for the presence or absence of elevated inflammatory response in the newborn.
PMCID: PMC3066075  PMID: 20921924
6.  Monocyte chemotactic protein 3 is a most effective basophil- and eosinophil-activating chemokine 
CC chemokines constitute a novel class of cytokines that attract and activate monocytes and lymphocytes, as well as basophil and eosinophil leukocytes, with distinct target cell profiles, and are believed to be involved in the regulation of different types of inflammation. The action of the recently identified monocyte chemotactic protein 3 (MCP- 3) on human basophil and eosinophil function was studied and compared with that of other CC chemokines. In basophils, MCP-3, MCP-1, RANTES, and macrophage inflammatory protein (MIP)-1 alpha all induced cytosolic- free calcium concentration ([Ca2+]i) changes and, with different efficacies, chemotaxis (RANTES = MCP-3 >> MCP-1 > MIP-1 alpha), histamine release (MCP-1 = MCP-3 >> RANTES > MIP-1 alpha), and leukotriene C4 formation, after IL-3 pretreatment (MCP-1 = MCP-3 >> RANTES > MIP-1 alpha). Thus, MCP-3 was as effective as MCP-1 as an inducer of mediator release, and as effective as RANTES as a stimulus of basophil migration. In contrast to MCP-1, MCP-3 was also a stimulus for eosinophils, and induced [Ca2+]i changes and chemotaxis as effectively as RANTES, which is the most potent chemotactic cytokine for these cells. Desensitization of the transient changes in [Ca2+]i was used to assess receptor usage. In basophils, stimulation with MCP-3 prevented responsiveness to MCP-1 and RANTES, but not to MIP-1 alpha. No single CC chemokine (except for MCP-3 itself) affected the response to MCP-3, however, which was prevented only when the cells were prestimulated with both MCP-1 and RANTES. In eosinophils, by contrast, cross-desensitization between RANTES and MCP-3 was obtained. RANTES and to a lesser extent MCP-3 also desensitized eosinophils toward MIP-1 alpha. The desensitization data suggest the existence of three chemokine receptors: (a) a MCP-1 receptor expressed on basophils but not eosinophils that is activated by MCP-1 and MCP-3; (b) a RANTES receptor in basophils and eosinophils that is activated by RANTES and MCP-3; and (c) a MIP-1 alpha receptor that is activated by MIP-1 alpha, RANTES and, more weakly, by MCP-3. This study shows that MCP-3 combines the properties of RANTES, a powerful chemoattractant, and MCP-1, a highly effective stimulus of mediator release, and thus has a particularly broad range of activities toward both human basophil and eosinophil leukocytes.
PMCID: PMC2191381  PMID: 7507512
7.  Protective Role of Matrix Metalloproteinase-9 in Ozone-Induced Airway Inflammation 
Environmental Health Perspectives  2007;115(11):1557-1563.
Exposure to ozone causes airway inflammation, hyperreactivity, lung hyper-permeability, and epithelial cell injury. An early inflammatory response induced by inhaled O3 is characterized primarily by release of inflammatory mediators such as cytokines, chemokines, and airway neutrophil accumulation. Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of oxidative lung disorders including acute lung injury, asthma, and chronic obstructive pulmonary disease.
We hypothesized that MMPs have an important role in the pathogenesis of O3-induced airway inflammation.
We compared the lung injury responses in either Mmp7- (Mmp7−/−) or Mmp9-deficient (Mmp9−/−) mice and their wild-type controls (Mmp7+/+, Mmp9+/+) after exposure to 0.3 ppm O3 or filtered air.
Relative to air-exposed controls, MMP-9 activity in bronchoalveolar lavage fluid (BALF) was significantly increased by O3 exposure in Mmp9+/+ mice. O3-induced increases in the concentration of total protein (a marker of lung permeability) and the numbers of neutrophils and epithelial cells in BALF were significantly greater in Mmp9−/− mice compared with Mmp9+/+ mice. Keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2 levels in BALF were also significantly higher in Mmp9−/− mice than in Mmp9+/+ mice after O3 exposure, although no differences in mRNA expression for these chemokines were found between genotypes. Mean BALF protein concentration and numbers of inflammatory cells were not significantly different between Mmp7+/+ and Mmp7−/− mice after O3 exposure.
Results demonstrated a protective role of MMP-9 but not of MMP-7, in O3-induced lung neutrophilic inflammation and hyperpermeability. The mechanism through which Mmp9 limits O3-induced airway injury is not known but may be via posttranscriptional effects on proinflammatory CXC chemokines including KC and MIP-2.
PMCID: PMC2072825  PMID: 18007984
chemokine; knockout mice; lung; MMP-9; O3; oxidant
8.  Cytokines and Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
The Journal of pediatrics  2011;159(6):919-925.e3.
To determine if selected pro-inflammatory and anti-inflammatory cytokines/mediators of inflammation reported to be related to development of cerebral palsy predict neurodevelopmental outcome in extremely low birth weight infants.
Study design
Infants with birth weights ≤ 1000 g (n=1067) had blood samples collected at birth and on days 3±1, 7±1, 14±3, and 21±3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on five cytokines (IL-1β, IL-8, TNF-α, RANTES, and IL-2) reported to be most predictive of CP in term and late preterm infants.
IL-8 was higher on days 0–4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, TNF-β, SIL-rα, MIP-1β) were found to be altered on days 0–4 in infants who developed CP.
CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.
PMCID: PMC3215787  PMID: 21798559
9.  Monocyte chemoattractant protein 1 and macrophage cyclooxygenase 2 expression in colonic adenoma 
Gut  2006;55(1):54-61.
Background and aims
Cyclooxygenase 2 (COX‐2) expression in subepithelial macrophages of colorectal adenoma has been suggested as the first in a series of steps leading to colorectal tumorigenesis. We tested the hypothesis that chemokines released from human colorectal adenoma epithelium might be involved in COX‐2 expression in macrophages of the lamina propria.
Endoscopic samples of sporadic colorectal adenomas were tested by enzyme linked immunosorbent assay for chemokines involved in macrophage chemotaxis. Localisation of adenoma macrophage chemoattractant protein 1 (MCP‐1) and COX‐2 were determined by immunohistochemistry. The effects of MCP‐1, in the presence or absence of celecoxib, on COX‐2 expression, and prostaglandin (PG) E2 and vascular endothelial growth factor (VEGF) release, were examined in human macrophages isolated from peripheral blood.
MCP‐1 levels were markedly higher in adenoma with mild‐moderate dysplasia (129.7 (19.9) pg/mg protein) and severe dysplasia (227.9 (35.4) pg/mg protein) than in normal colonic mucosa (55.8 (4.2) pg/mg protein). Other chemokine levels, macrophage inflammatory proteins (MIP)‐1α and MIP‐1β, and the chemokine regulated on activation of normal T cell expressed and secreted (RANTES) did not vary significantly between adenoma and normal mucosa. MCP‐1 levels in both adenoma and normal colonic mucosa increased significantly three hours after tissue cultivation in vitro. MCP‐1 immunoreactivity was restricted to the adenoma epithelium, with no reactivity seen in adjacent normal epithelial cells. MCP‐1 stimulated COX‐2 expression and PGE2 and VEGF release in human macrophages. Celecoxib, a selective COX‐2 inhibitor, inhibited MCP‐1‐induced PGE2 and VEGF release in macrophages. Addition of exogenous PGE2 reversed this inhibitory effect on VEGF release, suggesting that MCP‐1 in adenoma epithelial cells might be involved in COX‐2 expression and subsequent macrophage activation.
MCP‐1 in colorectal adenoma epithelial cells might be involved in macrophage migration and COX‐2 expression, leading to the subsequent development of colonic adenoma.
PMCID: PMC1856393  PMID: 16085694
cyclooxygenase; macrophage chemoattractant protein; adenoma; macrophage
10.  Chemokines in the limbal form of vernal keratoconjunctivitis 
The British Journal of Ophthalmology  2000;84(12):1360-1366.
BACKGROUND/AIMS—Chemokines are a family of low molecular weight cytokines that attract and activate leucocytes. The CC chemokines act on eosinophils, basophils, monocytes, and lymphocytes, suggesting that they play an important part in allergic diseases. The aims of this study were to investigate the expression of the CC chemokines, RANTES, eotaxin, monocyte chemotactic protein (MCP) 1, MCP-2, and MCP-3 in the conjunctiva of patients with vernal keratoconjunctivitis (VKC) and to determine the cellular source of these chemokines.
METHODS—Conjunctival biopsy specimens from nine subjects with active VKC, and six control subjects were studied by immunohistochemical techniques using a panel of monoclonal and polyclonal antibodies directed against RANTES, eotaxin, MCP-1, MCP-2, and MCP-3. The phenotype of inflammatory cells expressing chemokines was examined by sequential double immunohistochemistry.
RESULTS—In the normal conjunctiva, superficial epithelial cells showed a constitutive, weak cytoplasmic expression of eotaxin. Few inflammatory cells in the perivascular areas expressed RANTES, MCP-1, MCP-2, and MCP-3. In VKC specimens, the epithelium showed intense cytoplasmic eotaxin staining in all cells, and cytoplasmic RANTES staining mainly in the superficial layers. Furthermore, RANTES and eotaxin were expressed on the vascular endothelium mainly in the upper substantia propria. Compared with normal controls, VKC specimens showed significantly more inflammatory cells expressing RANTES, eotaxin, MCP-1, and MCP-3 (p<0.001, 0.0028, 0.0092, and <0.001, respectively). In VKC specimens, the numbers of inflammatory cells expressing RANTES were significantly higher than the numbers of inflammatory cells expressing eotaxin, MCP-1, and MCP-2 (all p values <0.001). Colocalisation studies revealed that the majority of inflammatory cells expressing chemokines were CD68 positive monocytes/macrophages.
CONCLUSIONS—These results demonstrate an increase in the expression of RANTES, eotaxin, MCP-1, and MCP-3 in the conjunctiva of patients with VKC compared with control subjects. These data suggest a potential role for these chemokines in the pathogenesis of VKC. Antagonists of chemokine receptors may provide new therapeutic modalities in VKC.

PMCID: PMC1723358  PMID: 11090473
11.  The Association of Early Blood Oxygenation with Child Development in Preterm Infants with Acute Respiratory Disorders 
The potential negative impact of early blood oxygenation on development of specific cognitive and motor outcomes in children born at very low birth weight (VLBW; 1000 − 1500g) has not been examined even though these infants are exposed to varying durations and amounts of oxygen as part of their neonatal care. While this is the largest group of preterm infants, they receive much less research attention than extremely low birth weight infants (ELBW < 1000g).
Although neonatologists are questioning the routine use of oxygen therapy for all neonates, research has focused primarily on the more medically fragile ELBW infants. To date there are no systematic studies available to guide decision making for oxygen supplementation for a large segment of the preterm infant population. The aim of the present study was to determine if there is an association between blood oxygenation in the first four hours of life and specific cognitive and motor skills in preterm infants with acute respiratory disorders but no severe intracranial insult using a selected cohort from a longitudinal study children recruited in 1991 and 1992 designed to examine the role of biological immaturity as defined by gestational age and parenting in development. From this cohort, 55 children had acute respiratory disorders without severe intracranial insult. Of these, 35 children had at least one partial pressure of oxygen obtained from arterial blood (PaO2) during the first four hours of life as part of their clinical care. Higher early PaO2 values were associated with lower impulse control and attention skills in the elementary school age period. Models that examined for relations between PaO2 values that also included birth weight and parenting quality across the first year of life revealed that higher PaO2 remained associated with impulse control but not attention skills. Birth weight was not associated with any outcomes. These results suggest that hyperoxia may be a risk factor for developmental problems that are not expressed until school age.
PMCID: PMC2288779  PMID: 17988819
very low birth weight; acute respiratory disorders; child development
12.  Neutralization of Macrophage Inflammatory Protein 2 (MIP-2) and MIP-1α Attenuates Neutrophil Recruitment in the Central Nervous System during Experimental Bacterial Meningitis 
Infection and Immunity  1999;67(5):2590-2601.
Chemokines are low-molecular-weight chemotactic cytokines that have been shown to play a central role in the perivascular transmigration and accumulation of specific subsets of leukocytes at sites of tissue damage. Using in situ hybridization (ISH), we investigated the mRNA induction of macrophage inflammatory protein 2 (MIP-2), MIP-1α, monocyte chemoattractant protein 1 (MCP-1), and RANTES. Challenge of infant rats’ brains with Haemophilus influenzae type b intraperitoneally resulted in the time-dependent expression of MIP-2, MIP-1α, MCP-1, and RANTES, which was maximal 24 to 48 h postinoculation. Immunohistochemistry showed significant increases in neutrophils and macrophages infiltrating the meninges, the ventricular system, and the periventricular area. The kinetics of MIP-2, MIP-1α, MCP-1, and RANTES mRNA expression paralleled those of the recruitment of inflammatory cells and disease severity. Administration of anti-MIP-2 or anti-MIP-1α antibodies (Abs) resulted in significant reduction of neutrophils. Administration of anti-MCP-1 Abs significantly decreased macrophage infiltration. Combined studies of ISH and immunohistochemistry showed that MIP-2- and MIP-1α-positive cells were neutrophils and macrophages. MCP-1-positive cells were neutrophils, macrophages, and astrocytes. Expression of RANTES was localized predominantly to resident astrocytes and microglia. The present study indicates that blocking of MIP-2 or MIP-1α bioactivity in vivo results in decreased neutrophil influx. These data are also the first demonstration that the C-C chemokine MIP-1α is involved in neutrophil recruitment in vivo.
PMCID: PMC116008  PMID: 10225925
13.  Semiquantitative analysis of intrahepatic CC-chemokine mRNas in chronic hepatitis C. 
Mediators of Inflammation  2004;13(5-6):357-359.
BACKGROUND: The mechanisms leading to hepatic injury in chronic hepatitis C virus (HCV) infection are only incompletely understood. Recent data propose a correlation of the intrahepatic expression of the CC chemokine RANTES and the degree of periportal and portal inflammatory liver damage. AIM: Here, we have studied the intrahepatic mRNA levels of CC chemokines RANTES together with that of other members of this chemokine family (MIP-1beta, MCP-1, and MCP-2) in chronic hepatitis C as compared with healthy controls. METHODS: Liver samples from 22 HCV-infected patients, nine individuals with primary biliary cirrhosis and from 12 normal controls were included into this study. Intrahepatic mRNA levels of CC chemokines RANTES, MIP-1beta, MCP-1, and MCP-2 were analyzed by a semi-quantitative reverse transcription/real-time polymerase chain reaction assay. RESULTS: In chronic HCV infection, intrahepatic RANTES mRNA levels were significantly higher than in non-infected controls (7.2-fold, p < 0.001) or in the disease control group (2.8-fold, p < 0.001) and higher levels of RANTES mRNA levels were observed in livers with an advanced stage of liver cell injury (histologic activity index > or = 6), although this difference was not statistically significant (p = 0.08). In contrast, mRNA levels of MIP-1beta (p = 0.021) and MCP-1 (p = 0.021) were significantly lower in HCV liver samples while MCP-2 expression was similar in all groups analyzed. CONCLUSION: The data support the concept of chemokines as mediators of liver cell injury in chronic hepatitis C.
PMCID: PMC1781586  PMID: 15770052
14.  Association Between Blood Spot Transforming Growth Factor-β and Patent Ductus Arteriosus in Extremely Low-Birth Weight Infants 
Pediatric cardiology  2012;34(1):149-154.
Permanent ductal closure involves anatomic remodeling, in which transforming growth factor (TGF)-β appears to play a role. Our objective was to evaluate the relationship, if any, between blood spot TGF-β on day 3 and day 7 of life and patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants. Prospective observational study involving ELBW infants (n = 968) in the National Institute of Child Health and Human Development Neonatal Research Network who had TGF-β measured on filter paper spot blood samples using a Luminex assay. Infants with a PDA (n = 493) were significantly more immature, had lower birth weights, and had higher rates of respiratory distress syndrome than those without PDA (n = 475). TGF-β on days 3 and 7 of life, respectively, were significantly lower among neonates with PDA (median 1,177 pg/ml [range 642–1,896]; median 1,386 pg/ml [range 868–1,913]) compared with others without PDA (median 1,334 pg/ml [range 760–2,064]; median 1,712 pg/ml [range 1,014–2,518 pg/ml]). The significant difference persisted when death or PDA was considered a composite outcome. TGF-β levels were not significantly different among subgroups of infants with PDA who were not treated (n = 51) versus those who were treated medically (n = 283) or by surgical ligation (n = 159). TGF-β was not a significant predictor of death or PDA (day 3 odds ratio [OR] 0.99, 95 % confidence interval [CI] 0.83–1.17; day 7 OR 0.88, 95 % CI 0.74–1.04) on adjusted analyses. Our results suggest that blood spot TGF-β alone is unlikely to be a reliable biomarker of a clinically significant PDA or its responsiveness to treatment.
PMCID: PMC3704212  PMID: 22684193
Transforming growth factor; Patent ductus arteriosus; Preterm; Neonate
15.  Levels of 25 cytokines in the first seven days of life in newborn infants 
BMC Research Notes  2013;6:547.
Novel methods for cytokine analysis allow for the simultaneous measurement of 25 cytokines in 50 μL serum or plasma. Data on values of most of these cytokines in non-infected newborn infants are lacking. We analyzed levels of 25 cytokines in the first week of life in non-infected preterm and term infants and related them to gestational age.
During the first week after birth, no trend over time was found in any of the cytokines, except for IL-1Ra and IL-6 where higher values were found in the first four hours. Between 24 and 72 hrs levels of IL-1Ra, IL-2, IL-8, IL-12, IL-13, IL-15, IL-17, IFNγ, MIP-1a, MCP-1, TNFα were lower in infants born after 30-32 wks compared to infants ≥36 wks; levels of IL-6, IL-10, IP-10 were lower in preterm infants of both 30–32 and 33–36 weeks. No difference between groups for any of the levels was found for IL-1b, IL-2r, IL-4, IL-5, IL-7, IFNa, MIP-1b, GM-CSF, Eotaxin and RANTES.
Levels of 25 interleukines are stable in the first week of life in non-infected infants. Infants born after 30-32 wks showed lower levels of fourteen cytokines compared to infants born after more then 36 wks. This indicates a lower stimulation or activation of Th-1 cells, monocytes and dendritic cells in these infants.
PMCID: PMC3878401  PMID: 24359685
Cytokines; Chemokines; Preterm-infants; Term-newborn
16.  Reliability of tumor markers, chemokines, and metastasis-related molecules in serum 
European cytokine network  2009;20(1):21-26.
There is a growing interest in the role that cancer biomarkers, metastasis-related molecules, and chemokines may play in the development and progression of various cancers. However, few studies have addressed the reliability of such biomarkers in healthy individuals over time. The objective of this study was to investigate the temporal reliability of multiple proteins in serum samples from healthy women who donated blood over successive years. Thirty five, postmenopausal women with two, repeated annual visits, and thirty, premenopausal women with three, repeated annual visits were randomly selected among eligible subjects from an existing, prospective cohort. Multiplexing Luminex xMAP™ technology was used to measure the levels of 55 serum proteins representing cancer antigens, chemokines, angiogenic and anti-angiogenic factors, proteases, adipokines, apoptotic molecules, and other markers in these women. The biomarkers with high detection rates (> 60%) and acceptable reliability (intraclass correlation coefficient, ICCs ≥ 0.55) using xMAP™ method were: cancer antigens: AFP, CA 15-3, CEA, CA-125, SCC, SAA; growth factors/related molecules: ErbB2, IGFBP-1; proteases and adhesion molecules: MMP-1, 8, 9, sE-selectin, human kallikreins (KLK) 8,10, ICAM-1, VCAM-1, chemokines: fractalkine, MCP-1,2, RANTES, MIP-1α, MIP-1β, Eotaxin, GRO-α, IP-10; inhibitors of angiogenesis: angiostatin and endostatin; adipokines leptin and resistin; apoptotic factor: Fas, and other proteins mesothelin, myeloperoxidase (MPO), and PAI-1. The rest of the biomarkers under investigation either had ICCs less than 0.55 or had low levels of detection (< 60%). These included cancer antigens: CA 19-9, CA 72-4, MICA, S100, TTR, ULBP1, ULBP2, ULBP3; proteases: MMP 2, 3, 7, 12, 13; chemokines: MCP-3, MIF, MIG; adipokines: leptin and resistin; apoptotic factors: FasL, DR5, Cyfra 21-1; and inhibitors of angiogenesis and other markers: thrombospondin and heat shock protein (HSP) 27. In conclusion, 34 out of the 55 biomarkers investigated were present in detectable levels in > 60% of the samples, and with an ICC ≥0.55, indicating that a single serum measurement can be used in prospective epidemiological studies using the xMAP™ method.
PMCID: PMC3001301  PMID: 19318317
reliability; tumor markers; chemokines; metastasis-related molecules; prospective cohort
17.  Exposure to Moderate Air Pollution during Late Pregnancy and Cord Blood Cytokine Secretion in Healthy Neonates 
PLoS ONE  2011;6(8):e23130.
Ambient air pollution can alter cytokine concentrations as shown in vitro and following short-term exposure to high air pollution levels in vivo. Exposure to pollution during late pregnancy has been shown to affect fetal lymphocytic immunophenotypes. However, effects of prenatal exposure to moderate levels of air pollutants on cytokine regulation in cord blood of healthy infants are unknown.
In a birth cohort of 265 healthy term-born neonates, we assessed maternal exposure to particles with an aerodynamic diameter of 10 µm or less (PM10), as well as to indoor air pollution during the last trimester, specifically the last 21, 14, 7, 3 and 1 days of pregnancy. As a proxy for traffic-related air pollution, we determined the distance of mothers' homes to major roads. We measured cytokine and chemokine levels (MCP-1, IL-6, IL-10, IL-1ß, TNF-α and GM-CSF) in cord blood serum using LUMINEX technology. Their association with pollution levels was assessed using regression analysis, adjusted for possible confounders.
Mean (95%-CI) PM10 exposure for the last 7 days of pregnancy was 18.3 (10.3–38.4 µg/m3). PM10 exposure during the last 3 days of pregnancy was significantly associated with reduced IL-10 and during the last 3 months of pregnancy with increased IL-1ß levels in cord blood after adjustment for relevant confounders. Maternal smoking was associated with reduced IL-6 levels. For the other cytokines no association was found.
Our results suggest that even naturally occurring prenatal exposure to moderate amounts of indoor and outdoor air pollution may lead to changes in cord blood cytokine levels in a population based cohort.
PMCID: PMC3149643  PMID: 21826232
18.  Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children 
Malaria Journal  2007;6:147.
Plasmodium falciparum can cause a diffuse encephalopathy known as cerebral malaria (CM), a major contributor to malaria associated mortality. Despite treatment, mortality due to CM can be as high as 30% while 10% of survivors of the disease may experience short- and long-term neurological complications. The pathogenesis of CM and other forms of severe malaria is multi-factorial and appear to involve cytokine and chemokine homeostasis, inflammation and vascular injury/repair. Identification of prognostic markers that can predict CM severity will enable development of better intervention.
Postmortem serum and cerebrospinal fluid (CSF) samples were obtained within 2–4 hours of death in Ghanaian children dying of CM, severe malarial anemia (SMA), and non-malarial (NM) causes. Serum and CSF levels of 36 different biomarkers (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGF basic protein, CRP, G-CSF, GM-CSF, IFN-γ, TNF-α, IP-10, MCP-1 (MCAF), MIP-1α, MIP-1β, RANTES, SDF-1α, CXCL11 (I-TAC), Fas-ligand [Fas-L], soluble Fas [sFas], sTNF-R1 (p55), sTNF-R2 (p75), MMP-9, TGF-β1, PDGF bb and VEGF) were measured and the results compared between the 3 groups.
After Bonferroni adjustment for other biomarkers, IP-10 was the only serum biomarker independently associated with CM mortality when compared to SMA and NM deaths. Eight CSF biomarkers (IL-1ra, IL-8, IP-10, PDGFbb, MIP-1β, Fas-L, sTNF-R1, and sTNF-R2) were significantly elevated in CM mortality group when compared to SMA and NM deaths. Additionally, CSF IP-10/PDGFbb median ratio was statistically significantly higher in the CM group compared to SMA and NM groups.
The parasite-induced local cerebral dysregulation in the production of IP-10, 1L-8, MIP-1β, PDGFbb, IL-1ra, Fas-L, sTNF-R1, and sTNF-R2 may be involved in CM neuropathology, and their immunoassay may have potential utility in predicting mortality in CM.
PMCID: PMC2186349  PMID: 17997848
19.  Effects of Phosphodiesterase 4 Inhibition on Alveolarization and Hyperoxia Toxicity in Newborn Rats 
PLoS ONE  2008;3(10):e3445.
Prolonged neonatal exposure to hyperoxia is associated with high mortality, leukocyte influx in airspaces, and impaired alveolarization. Inhibitors of type 4 phosphodiesterases are potent anti-inflammatory drugs now proposed for lung disorders. The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury.
Rat pups were placed under hyperoxia (FiO2>95%) or room air from birth, and received rolipram or its diluent daily until sacrifice. Mortality rate, weight gain and parameters of lung morphometry were recorded on day 10. Differential cell count and cytokine levels in bronchoalveolar lavage and cytokine mRNA levels in whole lung were recorded on day 6.
Rolipram diminished weight gain either under air or hyperoxia. Hyperoxia induced huge mortality rate reaching 70% at day 10, which was prevented by rolipram. Leukocyte influx in bronchoalveolar lavage under hyperoxia was significantly diminished by rolipram. Hyperoxia increased transcript and protein levels of IL-6, MCP1, and osteopontin; rolipram inhibited the increase of these proteins. Alveolarization was impaired by hyperoxia and was not restored by rolipram. Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count.
Although inhibition of phosphodiesterases 4 prevented mortality and lung inflammation induced by hyperoxia, it had no effect on alveolarization impairment, which might be accounted for by the aggressiveness of the model. The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization.
PMCID: PMC2563688  PMID: 18941502
20.  A Prospective Nested Case-Control Study of Dengue in Infants: Rethinking and Refining the Antibody-Dependent Enhancement Dengue Hemorrhagic Fever Model 
PLoS Medicine  2009;6(10):e1000171.
Analyses of a prospective case-control study of infant dengue by Daniel Libraty and colleagues casts doubt on the antibody-dependent enhancement model for dengue hemorrhagic fever.
Dengue hemorrhagic fever (DHF) is the severe and life-threatening syndrome that can develop after infection with any one of the four dengue virus (DENV) serotypes. DHF occurs almost exclusively in individuals with secondary heterologous DENV infections and infants with primary DENV infections born to dengue immune mothers. The widely accepted explanation for the pathogenesis of DHF in these settings, particularly during infancy, is antibody-dependent enhancement (ADE) of DENV infection.
Methods and Findings
We conducted a prospective nested case-control study of DENV infections during infancy. Clinical data and blood samples were collected from 4,441 mothers and infants in up to two pre-illness study visits, and surveillance was performed for symptomatic and inapparent DENV infections. Pre-illness plasma samples were used to measure the associations between maternally derived anti-DENV3 antibody-neutralizing and -enhancing capacities at the time of DENV3 infection and development of infant DHF.
The study captured 60 infants with DENV infections across a wide spectrum of disease severity. DENV3 was the predominant serotype among the infants with symptomatic (35/40) and inapparent (15/20) DENV infections, and 59/60 infants had a primary DENV infection. The estimated in vitro anti-DENV3 neutralizing capacity at birth positively correlated with the age of symptomatic primary DENV3 illness in infants. At the time of symptomatic DENV3 infection, essentially all infants had low anti-DENV3 neutralizing activity (50% plaque reduction neutralizing titers [PRNT50] ≤50) and measurable DENV3 ADE activity. The infants who developed DHF did not have significantly higher frequencies or levels of DENV3 ADE activity compared to symptomatic infants without DHF. A higher weight-for-age in the first 3 mo of life and at illness presentation was associated with a greater risk for DHF from a primary DENV infection during infancy.
This prospective nested case-control study of primarily DENV3 infections during infancy has shown that infants exhibit a full range of disease severity after primary DENV infections. The results support an initial in vivo protective role for maternally derived antibody, and suggest that a DENV3 PRNT50 >50 is associated with protection from symptomatic DENV3 illness. We did not find a significant association between DENV3 ADE activity at illness onset and the development of DHF compared with less severe symptomatic illness. The results of this study should encourage rethinking or refinement of the current ADE pathogenesis model for infant DHF and stimulate new directions of research into mechanisms responsible for the development of DHF during infancy.
Trial registration NCT00377754
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, dengue infects 50–100 million people living in tropical and subtropical areas. The four closely related viruses that cause dengue (DENV1–4) are transmitted to people through the bites of female Aedes aegypti mosquitoes, which acquire the viruses by feeding on the blood of an infected person. Many people who become infected with DENV have no symptoms but some develop dengue fever, a severe, flu-like illness that lasts a few days. Other people—about half a million a year—develop a potentially fatal condition called dengue hemorrhagic fever (DHF). In DHF, which can be caused by any of the DENVs, small blood vessels become leaky and friable. This leakiness causes nose and gum bleeds, bruising and, in the worst cases, failure of the circulatory system and death. There is no vaccine to prevent dengue and no specific treatment for dengue fever or DHF. However, with standard medical care—in particular, replacement of lost fluids—most people can survive DHF.
Why Was This Study Done?
DHF is increasingly common, but why do only some people develop DHF after infection with DENV? The widely accepted explanation for the development of DHF is “antibody-dependent enhancement” (ADE) of DENV infection. DHF occurs almost exclusively in two settings; (i) children and adults who become infected with a second DENV serotype after an initial “primary” DENV infection with a different serotype, and (ii) infants with primary DENV infections whose mothers have some DENV immunity. The ADE model suggests that in individuals who develop DHF, although there are some antibodies (proteins made by the immune system to fight infections) against DENV in their blood (in secondary heterologous infections, antibodies left over from the primary infection; in infants with primary infections, antibodies acquired from their mothers before birth), these antibodies cannot “neutralize” the virus. Instead, they bind to it and enhance its uptake by certain immune system cells, thus increasing viral infectivity and triggering an immunological cascade that results in DHF. In this prospective, nested case-control study, the researchers directly test the ADE model for infant DHF. In a prospective study, a group of people is selected and followed to see if they develop a disease; in a nested case-control study, each case is compared with people in the group who do not develop the disease.
What Did the Researchers Do and Find?
The researchers collected clinical data and blood samples from 4,441 mothers and their babies at up to two pre-illness study visits. They then followed the infants for a year to see which of them developed symptomatic and symptom-free DENV infections. Finally, they used the pre-illness blood samples to estimate the maternally derived anti-DENV antibody-neutralizing and -enhancing capacities in the infants at the time of DENV infection. 60 infants were infected with DENV—mainly DENV3—during the study. All but one infection was a primary infection. The infected infants showed a wide range of disease severity. Infants who had a high DENV3 neutralizing capacity at birth tended to develop symptomatic DENV3 infections later than infants who had a low DENV3 neutralizing capacity at birth. All the infants who developed a symptomatic DENV3 infection had a low estimated DENV3 neutralizing activity at the time of infection, and nearly all had measurable levels of DENV3 ADE activity. Infants who developed DHF did not have significantly higher frequencies or levels of DENV3 ADE activity than DENV3-infected infants with less severe symptoms.
What Do These Findings Mean?
These findings indicate that maternally derived anti-DENV3 antibody initially provides protection against dengue infections. That is, babies born to DENV immune mothers are protected against dengue infections by maternally derived antibodies. Over time, the level of these antibodies declines until eventually the infant becomes susceptible to DENV infections. However, the lack of a significant association between the estimated level of DENV3 ADE activity at illness onset and the development of DHF rather than a less severe illness throws doubt onto (but does not completely rule out) the current ADE pathogenesis model for infant DHF, at least for DENV3 infections. The results of this study, the researchers conclude, should encourage rethinking or refinement of the ADE model for infant DHF and should promote further prospective studies into the development of DHF during infancy.
Additional Information
Please access these Web sites via the online version of this summary at provides review articles, news, opinions, research articles, and reports on dengue (in English)
The US Centers for Disease Control and Prevention provide detailed information about dengue fever and dengue hemorrhagic fever (in English and Spanish)
The World Health Organization provides information on dengue fever and dengue hemorrhagic fever around the world (in several languages)
Links to additional resources about dengue are provided by MedlinePlus (in English and Spanish)
Wikipedia has a page on antibody-dependent enhancement of viral infections (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2762316  PMID: 19859541
21.  Perinatal systemic inflammatory responses of growth-restricted preterm newborns 
Acta paediatrica (Oslo, Norway : 1992)  2013;102(10):e439-e442.
To compare the early postnatal pattern of systemic inflammation in growth-restricted infants born before the 28th week of gestation to that of appropriately grown peers.
We measured the concentrations of 25 inflammation-related proteins in blood spots collected from 939 newborns during the first 2 postnatal weeks. We calculated the odds ratios (99% confidence intervals) that concentrations would be in the highest quartile.
Severely growth-restricted infants (birth weight Z-score < -2) were not at increased risk of systemic inflammation shortly after birth. On postnatal day 14, however, they were significantly more likely than their peers to have a CRP, IL-1β, IL-6, TNF-α, IL-8, MCP-4, ICAM-1, ICAM-3, E-SEL, MMP-9, VEGF-R2, and/or IGFBP-1 concentration in the highest quartile. These increased risks could not be attributed to delivery indication, bacteremia, or duration of ventilation.
Growth-restricted preterm newborns appear to be at increased risk of elevated concentrations of inflammation-associated proteins by postnatal day 14.
PMCID: PMC3773878  PMID: 23819682
growth-restricted; inflammation; IUGR; neonate; preterm
22.  Raised plasma concentration and ex vivo production of inflammatory chemokines in patients with systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2005;65(2):209-215.
Chemokines are involved in leucocyte chemotaxis. Infiltrating leucocytes play an important role of tissue injury in systemic lupus erythematosus (SLE).
To investigate the role of inflammatory chemokines and their association with interleukin 18 (IL18) in SLE pathogenesis and disease activity.
Plasma concentrations and ex vivo peripheral blood mononuclear cell production of inflammatory chemokines IP‐10, RANTES, MIG, MCP‐1, TARC, IL8, and GROα, and proinflammatory cytokines IL18, IFNγ, IL2, IL4, and IL10 were assayed in 80 SLE patients with or without renal disease and 40 healthy controls by immunofluorescence flow cytometry and enzyme linked immunosorbent assay.
Plasma IP10, RANTES, MIG, MCP‐1, GROα, and IL18 concentrations in all SLE patients were higher than in controls, and correlated significantly with SLEDAI score (all p<0.05). In SLE patients without renal disease, IP10, RANTES, MIG, MCP‐1, IL8, and IL18 correlated positively with SLEDAI score, while in those with renal derangement, IP10, IL8, IL10, and IL18 correlated with disease activity (all p<0.05). Plasma IL18 concentration correlated positively with IP10, MIG, GROα, and IL8 in all SLE patients (all p<0.005). Mitogen induced increases in ex vivo production of IP10, MCP‐1, TARC, IFNγ, IL4, and IL10 were higher in all SLE patients regardless of their difference in disease activity (all p<0.05). Patients with renal disease had an augmented ex vivo release of RANTES.
The correlation of raised plasma concentration and ex vivo production of inflammatory chemokines with disease activity, and their association with IL18, supports the view that chemotaxis of Th1/Th2 lymphocytes and neutrophils is important in SLE pathogenesis.
PMCID: PMC1798029  PMID: 15975968
systemic lupus erythematosus; SLEDAI; inflammatory chemokines; IL18
23.  Risk Factors for Post-NICU Discharge Mortality Among Extremely Low Birth Weight Infants 
The Journal of Pediatrics  2012;161(1):70-74.e2.
To evaluate maternal and neonatal risk factors associated with post-neonatal intensive care unit (NICU) discharge mortality among ELBW infants.
Study design
This is a retrospective analysis of extremely low birth weight (<1,000 g) and <27 weeks' gestational age infants born in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network sites from January 2000 to June 2007. Infants were tracked until death or 18–22 months corrected age. Infants who died between NICU discharge and the 18–22 month follow-up visit were classified as post-NICU discharge mortality. Association of maternal and infant risk factors with post-NICU discharge mortality was determined using logistic regression analysis. A prediction model with six significant predictors was developed and validated.
5,364 infants survived to NICU discharge. 557 (10%) infants were lost to follow-up, and 107 infants died following NICU discharge. Post-NICU discharge mortality rate was 22.3 per 1000 ELBW infants. In the prediction model, African-American race, unknown maternal health insurance, and hospital stay ≥120 days significantly increased risk, and maternal exposure to intra-partum antibiotics was associated with decreased risk of post-NICU discharge mortality.
We identified African-American race, unknown medical insurance and prolonged NICU stay as risk factors associated with post-NICU discharge mortality among ELBW infants.
PMCID: PMC3366175  PMID: 22325187
extremely preterm infants; discharge; mortality; predictive model
24.  Maternal exposure to combustion generated PM inhibits pulmonary Th1 maturation and concomitantly enhances postnatal asthma development in offspring 
Epidemiological studies suggest that maternal exposure to environmental hazards, such as particulate matter, is associated with increased incidence of asthma in childhood. We hypothesized that maternal exposure to combustion derived ultrafine particles containing persistent free radicals (MCP230) disrupts the development of the infant immune system and results in aberrant immune responses to allergens and enhances asthma severity.
Pregnant C57/BL6 mice received MCP230 or saline by oropharyngeal aspiration on gestational days 10 and 17. Three days after the second administration, blood was collected from MCP230 or saline treated dams and 8-isoprostanes in the serum were measured to assess maternal oxidative stress. Pulmonary T cell populations were assayed in the infant mice at six days, three and six weeks of postnatal age. When the infant mice matured to adults (i.e. six weeks of age), an asthma model was established with ovalbumin (OVA). Airway inflammation, mucus production and airway hyperresponsiveness were then examined.
Maternal exposure to MCP230 induced systemic oxidative stress. The development of pulmonary T helper (Th1/Th2/Th17) and T regulatory (Treg) cells were inhibited in the infant offspring from MCP230-exposed dams. As the offspring matured, the development of Th2 and Treg cells recovered and eventually became equivalent to that of offspring from non-exposed dams. However, Th1 and Th17 cells remained attenuated through 6 weeks of age. Following OVA sensitization and challenge, mice from MCP230-exposed dams exhibited greater airway hyperresponsiveness, eosinophilia and pulmonary Th2 responses compared to offspring from non-exposed dams.
Our data suggest that maternal exposure to MCP230 enhances postnatal asthma development in mice, which might be related to the inhibition of pulmonary Th1 maturation and systemic oxidative stress in the dams.
PMCID: PMC3717277  PMID: 23856009
Maternal exposure; Particulate matter; Offspring; Asthma
25.  Protective antibody therapy is associated with reduced chemokine transcripts in herpes simplex virus type 1 corneal infection. 
Journal of Virology  1996;70(2):1277-1281.
Herpes simplex virus type 1 (HSV-1) infection on the murine cornea induces an intense inflammatory response which can lead to blindness. This disease, known as herpes stromal keratitis, can be prevented by the timely passive transfer of monoclonal antibody specific for viral glycoprotein D (gD). Precisely how antibody treatment prevents excessive corneal inflammation is not known. In this study we investigated whether chemokine mRNA expression is inhibited by antibody treatment. Total cellular RNAs isolated from normal corneas and at various times after virus infection were analyzed via reverse transcription-PCR for mRNA coding for seven different chemokines. Constitutive levels of IP-10, KC, MIP-2, MCP-1, MIP-1 beta, and RANTES mRNA were detected in uninfected corneas of BALB/c mice. When the cornea was mechanically traumatized, message for all six chemokines was transiently elevated above constitutive levels. In contrast, HSV-1 infection resulted in prolonged enhanced chemokine message expression. The kinetics of mRNA accumulation was distinctive for each chemokine analyzed. MIP-1 alpha message, not detected constitutively, was not evident until day 7 postinfection. Administration of anti-HSV gD monoclonal antibody 1 day after infection was associated with reduced message for MIP-2, MCP-1, MIP-1 alpha, and MIP-1 beta. IP-10, KC, and RANTES messages were not altered. Collectively, our results suggest that anti-gD treatment may protect, at least in part, by inhibiting production of chemokines believed to promote inflammation.
PMCID: PMC189943  PMID: 8551595

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