Inflammation-related proteins in the blood of extremely low gestational age newborns. The contribution of inflammation to the appearance of developmental regulation

Neurology Department, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
Cytokine (Impact Factor: 2.66). 10/2010; 53(1):66-73. DOI: 10.1016/j.cyto.2010.09.003
Source: PubMed


We wanted to assess to what extent concentrations of circulating proteins appear to be developmentally regulated, and to what extent such regulation is influenced by intra-uterine inflammation.
We measured 22 proteins in blood obtained on postnatal days 1, 7, and 14 from 818 children born before the 28th week of gestation for whom we also had information about placenta morphology.
Within the narrow gestational age range of this sample, some protein concentrations increase in blood with increasing gestational age. More commonly, the concentrations of inflammation-related proteins decrease with increasing gestational age. We observed this inverse pattern both in children whose placenta was and was not inflamed. CONCLUSIONS/INFERENCES: Regardless of whether or not the placenta is inflamed, the concentrations of inflammation-related proteins in early blood specimens appear to be developmentally regulated with the most common pattern being a decrease with increasing gestational age.

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    • "Details about elution of proteins from blood spots and measurement of the proteins with the Meso Scale Discovery (MSD) electrochemiluminescence system are provided elsewhere [24]. Validated by comparisons with traditional ELISA [25] [26], this system has inter-assay variations that are invariably less than 20%. "
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    ABSTRACT: To explore the relationships between blood gas derangements and blood concentrations of inflammation-related proteins shortly after preterm birth. Observational cohort. Fourteen neonatal intensive care units. Seven hundred and forty five infants born before the 28th week of gestation who were classified by their blood gas derangements during the first three postnatal days and by the concentrations of 25 proteins in their blood on days 1, 7, and 14. We classified these newborns by whether or not they had a highest or lowest PaO2, PCO2, and lowest pH in the most extreme quartile, and by whether or not they had a protein concentration in the highest quartile. Blood gas derangements on two days were much more likely to be accompanied or followed by sustained or recurrent systemic inflammation than a derangement on only one day. This was most evident for acidemia, and slightly less so for hypercapnia. Our finding that protein concentration patterns indicative of systemic inflammation are associated with several blood gas derangements raises the possibility that organ damage attributed to these derangements might be accompanied by or involve an inflammatory response.
    Full-text · Article · Aug 2011 · Cytokine
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    • "Systemic adaptive and innate immune responses of the human neonates are known to differ from the adult's one in several ways, such as a bias towards Th2 response, and peripheral blood monocyte stimulation from pathogens leading to higher IL-6, and IL-10 responses, but lower TNF-α expression than in the adults [58,59]. Certain developmental comparisons have already been performed between neonatal and adult neuroinflammatory responses and across neonatal period [60,61]. For instance, a "window of susceptibility" to intracerebral IL-1β exposure was detected in juvenile (2-6 week-old) as opposed to neonatal (P1) or adult (P90) rats, with juvenile rats displaying a peculiar age-dependent hyper-response in term of neutrophil infiltration and neural cell damage [62-64]. "
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    ABSTRACT: Preterm and term newborns are at high risk of brain damage as well as subsequent cerebral palsy and learning disabilities. Indeed, hypoxia-ischemia (HI), pathogen exposures, and associated intracerebral increase of pro-inflammatory cytokines have all been linked to perinatal brain damage. However, the developmental effects of potential variations of pro- and anti-inflammatory cytokine ratios remain unknown. Using rat models of perinatal brain damage induced by exposures to lipopolysaccharide (LPS) and/or HI at distinct levels of maturity, we compared cytokine expression at stages of cerebral development equivalent to either preterm (postnatal day 1, P1) or term (P12) newborns. At P1, expression of anti-inflammatory cytokine within the brain was either not modulated (IL-6, IL-10) or down-regulated (IL-1ra, TGF-β1) by HI, LPS or LPS+HI. In contrast, there was at P12 an up-regulation of all anti-inflammatory cytokines studied in HI or LPS+HI condition, but not after LPS exposure. Interestingly, IL-1β was the main pro-inflammatory cytokine up-regulated moderately at P1, and strongly at P12, with a weak co-expression of TNF-α observed mainly at P12. These age-dependant inflammatory reactions were also accompanied, under HI and LPS+HI conditions, at P12 only, by combined: (i) expression of chemokines CINC-1 and MCP-1, (ii) blood-brain barrier (BBB) leakage, and (iii) intracerebral recruitment of systemic immune cells such as neutrophils. In contrast, sole LPS induced IL-1β responses mainly within white matter at P1 and mainly within gray matter at P12, that were only associated with early MCP-1 (but no CINC-1) induction at both ages, without any recruitment of neutrophils and CD68+ cells. HI and LPS+HI induce pro-inflammatory oriented immune responses in both preterm and term like brains, with a maximal inflammatory response triggered by the combination of LPS+HI. The profile of these neuroinflammatory responses presented striking variations according to age: no or down-regulated anti-inflammatory responses associated with mainly IL-1β release in preterm-like brains (P1), in sharp contrast to term-like brains (P12) presenting stronger anti-and pro-inflammatory responses, including both IL-1β and TNF-α releases, and BBB leakage. These developmental-dependant variations of neuroinflammatory response could contribute to the differential pattern of brain lesions observed across gestational ages in humans. This also highlights the necessity to take into consideration the maturation stage, of both brain and immune systems, in order to develop new anti-inflammatory neuroprotective strategies.
    Full-text · Article · May 2011 · Journal of Neuroinflammation

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