| 1. |
- Doverhag, Christina, 1979, et al.
(author)
-
Galectin-3 contributes to neonatal hypoxic-ischemic brain injury.
- 2010
-
In: Neurobiology of disease. - : Elsevier BV. - 1095-953X .- 0969-9961. ; 38:1, s. 36-46
-
Journal article (peer-reviewed)abstract
- Inflammation induced by hypoxia-ischemia (HI) contributes to the development of injury in the newborn brain. In this study we investigated the role of galectin-3, a novel inflammatory mediator, in the inflammatory response and development of brain injury in a mouse model for neonatal HI. Galectin-3 gene and protein expression was increased after injury and galectin-3 was located in activated microglia/macrophages. Galectin-3 deficient mice (gal3-/-) were protected from injury particularly in hippocampus and striatum. Microglia accumulation was increased in the gal3-/-mice but accompanied by decreased levels of total matrix metalloproteinase (MMP)-9 and nitrotyrosine. The protection and increase in microglial infiltration was more pronounced in male gal3-/-mice. Trophic factors and apoptotic markers did not significantly differ between groups. In conclusion, galectin-3 contributes to neonatal HI injury particularly in male mice. Our results indicate that galectin-3 exerts its effect by modulating the inflammatory response.
|
|
| 2. |
- Doverhag, Christina, 1979
(author)
-
Inflammation in experimental neonatal brain injury and in a clinical study of preterm birth; involvement of galectin-3 and free radical formation
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- Introduction; Intrauterine infection/inflammation is associated with preterm delivery (PTD) and severe neonatal morbidity. Inflammation is also important in the secondary neurotoxic cascade leading to perinatal brain injury. The aims were to investigate (a) the novel inflammatory marker galectin-3 that affects accumulation, apoptosis and activation of inflammatory cells and (b) free radical formation in particular by the enzyme NADPH-oxidase responsible for free radical formation in inflammatory cells, in threatening PTD (III) and in the development of experimental perinatal brain injury (I,II). Materials and methods; Amniotic fluid (AF) and placentas were obtained from 83 women with threatening PTD presenting with preterm labour (PTL) or premature prelabour rupture of membranes (pPROM) and from 15 term controls. AF was analysed for galectin-3, ascorbyl radicals and antioxidative capacity (AOC) and results were correlated to signs of intrauterine infection/inflammation, PTD and severe neonatal morbidity (III). In the experimental studies, models of term hypoxia-ischemia (HI) (I,II) and of excitotoxic white matter injury (I) were used in knock-out (KO) mice for galectin-3 (II) and gp91phox (a subunit in NADPH-oxidase) (I) and together with two inhibitors of NADPH oxidase (I). Lesion size, inflammation (microglia accumulation, inflammatory mediators), free radical formation, apoptosis and trophic factors were studied. In vitro studies were used to investigate free radical formation in microglial cells (I) and the effect of AF on pre-activated neutrophils (III). Results; Galectin-3, ascorbyl radicals and AOC were detected in all AF samples. Women with threatening PTD and infection/inflammation had higher levels of galectin-3 and slow AOC but lower levels of ascorbyl radicals than term controls but without correlation to PTD. Mothers of girls had higher levels galectin-3 than mothers of boys. AF also quenched free radical formation in primed neutrophils in vitro. Women with PTL did not differ from women with pPROM. Only AOC was increased in mothers to infants with severe morbidity (III). After experimental HI, mRNA expression of galectin-3 and NADPH-oxidase subunits (I,II) as well as galectin-3 protein expression were increased (II). Galectin-3 KO mice had reduced injury but increased microglial density and reduced expression of inflammatory factors (MMP-9) and markers for oxidative stress (nitrotyrosine). The protection was more pronounced in males. Apoptosis was altered in un-operated KO mice but not after HI. No difference was seen for trophic factors (II). Pharmacological inhibition of NADPH-oxidase reduced free radical formation in vitro and markers of oxidative stress in vivo, but resulted in an increase in apoptotic markers and lesion size after excitotoxic injury. Genetic inhibition did not reduce injury but resulted in an increase of the inflammatory markers galectin-3 and IL-1β (I). Conclusion; Galectin-3 is increased in women with threatening PTD and associated infection/inflammation,but our findings suggest a strong antioxidative capacity and not an increased oxidative stress as previously suggested (III). Galectin-3 contributes to neonatal brain injury by modulating the inflammatory response rather than affecting apoptosis or trophic factors and the mechanisms may be sex dependent (II). Contrary to findings in the adult brain, perinatal brain injury was unaltered or aggravated after genetic and pharmacological NADPH-oxidase inhibition (I).
|
|
| 3. |
- Doverhag, Christina, 1979, et al.
(author)
-
Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice
- 2008
-
In: Neurobiology of Disease. - : Elsevier BV. - 1095-953X .- 0969-9961. ; 31:1, s. 133-44
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Inflammation and reactive oxygen species (ROS) are important in the development of perinatal brain injury. The ROS-generating enzyme NADPH oxidase (Nox2) is present in inflammatory cells and contributes to brain injury in adult animal models. HYPOTHESIS: NADPH oxidase contributes to ROS formation and development of injury in the immature brain and inhibition of NADPH oxidase attenuates perinatal brain injury. METHODS: We used animal models of term hypoxia-ischemia (HI) (P9 mice) as well as ibotenate-induced excitotoxic injury (P5 mice) mimicking features of periventricular leukomalacia in preterm infants. In vitro microglia cell cultures were used to investigate NADPH oxidase-dependent ROS formation. In vivo we determined the impact 1) of HI on NADPH oxidase gene expression 2) of genetic (gp91-phox/Nox2 knock-out) and 3) of pharmacological NADPH oxidase inhibition on HI-induced injury and NMDA receptor-mediated excitotoxic injury, respectively. Endpoints were ROS formation, oxidative stress, apoptosis, inflammation and extent of injury. RESULTS: Hypoxia-ischemia increased NADPH oxidase subunits mRNA expression in total brain tissue in vivo. In vitro ibotenate increased NADPH oxidase-dependent formation of reactive oxygen species in microglia. In vivo the inhibition of NADPH oxidase did not reduce the extent of brain injury in any of the animal models. In contrast, the injury was increased by inhibition of NADPH oxidase and genetic inhibition was associated with an increased level of galectin-3 and IL-1beta. CONCLUSION: NADPH oxidase is upregulated after hypoxia-ischemia and activated microglia cells are a possible source of Nox2-derived ROS. In contrast to findings in adult brain, NADPH oxidase does not significantly contribute to the pathogenesis of perinatal brain injury. Results obtained in adult animals cannot be transferred to newborns and inhibition of NADPH oxidase should not be used in attempts to attenuate injury.
|
|
| 4. |
- Holst, Rose-Marie, 1946, et al.
(author)
-
Expression of cytokines and chemokines in cervical and amniotic fluid: Relationship to histological chorioamnionitis
- 2007
-
In: J Matern Fetal Neonatal Med. - : Informa UK Limited. ; 20:12, s. 885-893
-
Journal article (peer-reviewed)abstract
- Objective. To correlate cervical and amniotic fluid cytokines and macrophage-related chemokines to the development of histological chorioamnionitis (HCA) in patients with preterm labor (PTL) and preterm prelabor rupture of the membranes (PPROM). Study design. Cervical and amniotic fluid interleukin (IL)-6, IL-8, IL-18, monocyte chemotactic protein (MCP)-1, MCP-2, and MCP-3 from pregnant women (at
|
|
