Inflammatory Gene Profiling in the Developing Mouse Brain after Hypoxia-Ischemia

Hedtjärn, Maj; Mallard, Carina; Hagberg, Henrik

doi:10.1097/01.wcb.0000141559.17620.36

Cited by 95 publications

(11 citation statements)

References 86 publications

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“…DAP12 was co-expressed with microglia in the brain parenchyma, and this agrees with previous findings in the normal neonatal mouse brain [43] and in the rodent model of HI that is more representative of the type of brain injury seen in full-term infants [27]. The expression of DAP12 is found not only in injured areas but also in the meninges.…”

Section: Discussionsupporting

confidence: 89%

“…HI-induced injury to the immature brain has been found to induce the expression of various genes related to immune responses and inflammation, including macrophage and microglia-related genes, T-lymphocyte–related genes, and cytokines [27]. In addition, inflammatory mediators have been suggested to contribute to injury after HI in the immature brain [28] at a stage corresponding to human term and near-term infants.…”

Section: Introductionmentioning

confidence: 99%

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The immune response after hypoxia-ischemia in a mouse model of preterm brain injury

Albertsson

Duan

et al. 2014

J Neuroinflammation

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BackgroundPreterm brain injury consists primarily of periventricular leukomalacia accompanied by elements of gray-matter injury, and these injuries are associated with cerebral palsy and cognitive impairments. Inflammation is believed to be an important contributing factor to these injuries. The aim of this study was to examine the immune response in a postnatal day (PND) 5 mouse model of preterm brain injury induced by hypoxia-ischemia (HI) that is characterized by focal white and gray-matter injury.MethodsC57Bl/6 mice at PND 5 were subjected to unilateral HI induced by left carotid artery ligation and subsequent exposure to 10% O2 for 50 minutes, 70 minutes, or 80 minutes. At seven days post-HI, the white/gray-matter injury was examined. The immune responses in the brain after HI were examined at different time points after HI using RT-PCR and immunohistochemical staining.ResultsHI for 70 minutes in PND 5 mice induced local white-matter injury with focal cortical injury and hippocampal atrophy, features that are similar to those seen in preterm brain injury in human infants. HI for 50 minutes resulted in a small percentage of animals being injured, and HI for 80 minutes produced extensive infarction in multiple brain areas. Various immune responses, including changes in transcription factors and cytokines that are associated with a T-helper (Th)1/Th17-type response, an increased number of CD4+ T-cells, and elevated levels of triggering receptor expressed on myeloid cells 2 (TREM-2) and its adaptor protein DNAX activation protein of 12 kDa (DAP12) were observed using the HI 70 minute preterm brain injury model.ConclusionsWe have established a reproducible model of HI in PND 5 mice that produces consistent local white/gray-matter brain damage that is relevant to preterm brain injury in human infants. This model provides a useful tool for studying preterm brain injury. Both innate and adaptive immune responses are observed after HI, and these show a strong pro-inflammatory Th1/Th17-type bias. Such findings provide a critical foundation for future studies on the mechanism of preterm brain injury and suggest that blocking the Th1/Th17-type immune response might provide neuroprotection after preterm brain injury.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

The immune response after hypoxia-ischemia in a mouse model of preterm brain injury

Albertsson

Duan

et al. 2014

J Neuroinflammation

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“…Neonatal HI induces a cerebral inflammatory response including the production of cerebral inflammatory cytokines and chemokines and activation and recruitment of neutrophils and macrophages from the circulation to the brain [19,20,21,22,23,24,25,26,27,28,29]. This inflammatory response to neonatal HI is thought to result in additional cerebral damage [30,31].…”

Section: Introductionmentioning

confidence: 99%

Cerebral and Hepatic Inflammatory Response after Neonatal Hypoxia-Ischemia in Newborn Rats

Bonestroo¹,

Nijboer²,

Velthoven³

et al. 2013

Dev Neurosci

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Background: Neonatal encephalopathy induced by perinatal asphyxia is a serious condition associated with high mortality and morbidity. Inflammation after the insult is thought to contribute to brain injury. This inflammatory response to hypoxia-ischemia (HI) may not only occur in the brain but also in peripheral organs. The aim of the present study was to investigate the effect of neonatal HI on the inflammatory response in the liver in comparison to inflammation in the brain. Methods: HI was induced in P7 Wistar rats by unilateral carotid artery occlusion and hypoxia. Cytokine and chemokine mRNA levels were determined in the brain and liver by quantitative PCR. Polarization of brain macrophages to the M1/M2-like phenotype and infiltration of neutrophils were characterized by immunohistochemistry. Results: 3 h after HI, an upregulation of the proinflammatory cytokines TNF-α and IL-1β and anti-inflammatory IL-10 was observed in the ipsilateral hemisphere of the brain compared to mRNA levels in sham-operated animals. Additionally, cerebral CINC-1 and MCP-1 mRNA expressions were increased. We also observed increased numbers of macrophages/microglia of the M1-like phenotype as well as a small increase in granulocyte influx in the ipsilateral hemisphere. Conversely, in the liver 3 h after HI, a downregulation of TNF-α, IL-1β, and MCP-1 and a trend towards an upregulation of IL-10 were observed compared to mRNA levels of sham-operated animals. However, hepatic CINC-1 expression was increased compared to levels in sham-operated animals. Following systemic hypoxia only, no significant changes in the expression of TNF-α, CINC-1 or MCP-1 were observed in the liver compared to sham-operated littermates, except for an upregulation in hepatic IL-1β expression 3 h after hypoxia. Twenty-four hours after insult, cerebral ipsilateral TNF-α, MCP-1 and CINC-1 mRNA expression was still increased, together with an increase in TGF-β expression. Moreover, an increase in macrophages/microglia of the M1-like phenotype was observed together with the appearance of macrophages/microglia of the M2-like phenotype around the cerebral lesion as well as an increase in granulocyte influx in comparison to 3 h after HI. In the liver, 24 h after HI, cytokine and chemokine responses were similar to mRNA levels in sham-operated animals except for a decrease in IL-10 and MCP-1. Conclusion: We describe for the first time that brain damage following neonatal HI induces an early downregulation of the proinflammatory response in the liver. HI induces an early proinflammatory response in the brain with a concomitant increase in influx of neutrophils and polarization of macrophages/microglia to the M1-like phenotype starting at 3 h and increasing up to 24 h after HI. The inflammatory state of the brain changes after 24 h, with an increase in the anti-inflammatory cytokine TGF-β together with the appearance of macrophages/microglia of the M2-like phenotype. The downregulation of proinflammatory cytokines in the liver is not due to systemic hypoxia only, but i...

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“…Следующим важным фактором ГИП является воспаление. Целый ряд исследований отслежи-вает связь ГИП с повышенным уровнем воспалительных цитокинов [58][59][60], а также с активацией генов воспа-ления [61]. Наиболее важную роль воспаление играет во второй фазе ГИП (от 6 до 48 ч).…”

Section: обзор литературыunclassified

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

Каркашадзе¹,

Аникин²,

Зимина³

et al. 2016

Pediatr. farmakol.

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ВВЕДЕНИЕ Общемировой научно-технический прогресс в отно-шении исследовательских технологий за последние де-сятилетия привел к качественному и количественно-му скачку нейронаук. Наиболее активно наполняется новыми данными поле фундаментальных представлений о развитии головного мозга, что обусловливает интересы ученых к таким областям медицины, как перинатальная неврология и неврология раннего возраста. Несмотря на расширение представлений о вкладе генетической составляющей, по-прежнему большое внимание уделяет-ся изучению прямых патофизиологических механизмов гипоксически-ишемических поражений (ГИП) головного мозга у новорожденных. К настоящему моменту накоплен массив новых данных в этой области, что подталкивает медицину к внедрению передовых лечебных технологий.Цель работы -провести литературный обзор совре-менных научных данных о механизмах гипоксически-ише-мических повреждений мозга у новорожденных и разра-батываемых на их основании новых методов лечения. ПАТОФИЗИОЛОГИЧЕСКИЕ МЕХАНИЗМЫ ГИПОКСИЧЕСКИ-ИШЕМИЧЕСКИХ ПОРАЖЕНИЙТрадиционно основные лечебные тактики в острый период гипоксически-ишемических перинатальных поражений головного мозга (ГИППГМ) предусма-тривают медикаментозное поддержание сердечно-легочных функций и противосудорожную защиту [1]. Послед ние достижения в раскрытии патофизиологи-ческих механизмов непосредственно ГИП дают опору для поиска и внедрения новых лечебных технологий. У доношенных детей основным прямым механизмом ГИП является внутриутробная асфиксия, вызванная проблемами кровообращения, в том числе в области плацентарных артерий, отслойкой плаценты или вос-палительным процессом. За этим следуют снижение объема кислорода и углекислого газа в крови и тяже-лый лактат-ацидоз. Выраженное снижение сердечного выброса в условиях гипоксии, называемое гипоксией-ишемией, в течение 12-36 ч приводит к поражению головного мозга [2].

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Inflammatory Gene Profiling in the Developing Mouse Brain after Hypoxia-Ischemia

Cited by 95 publications

References 86 publications

The immune response after hypoxia-ischemia in a mouse model of preterm brain injury

The immune response after hypoxia-ischemia in a mouse model of preterm brain injury

Cerebral and Hepatic Inflammatory Response after Neonatal Hypoxia-Ischemia in Newborn Rats

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

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