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

Abstract

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...

Delayed ALK5 inhibition improves functional recovery in neonatal brain injury

“…Indeed, in contrast to the cerebral pro-inflammatory response, cerebral ischemia depresses the peripheral immune system. 26 This phenomenon has been referred to as stroke or CNS injury-induced immunodepression syndrome 27,28 and is attributed to cerebral production of pro-inflammatory cytokines and to local brain damage, which causes suppression of innate and adaptive immunity. In light of the reduced brain damage and reduced pro-inflammatory cytokines expression in SB505124 treated rats, it should not be surprising that peripheral lymphoid organs were not adversely affected.…”

Administration of Umbilical Cord Blood Cells Transiently Decreased Hypoxic-Ischemic Brain Injury in Neonatal Rats

“…The treatment effect might be through trophic factors secreted by the cells [41]. The extent of brain damage can be influenced by the peripheral inflammatory response [42]. Modulating peripheral inflammation can be a therapeutic target.…”

MSCS in Scenarios of Infection and Inflammation: Focus on Neonatal Diseases

“…This confirms the notion that MSCs are most effective when administered in the context of inflammation. Accordingly, the combined administration of both ↑ in murine HI cerebral tissue [37] ↑ Th1 and Th17 in murine HI cerebral tissue [34] ↓ Treg in murine HI cerebral tissue [34] BPD ↓ M1 macrophages in murine lung [38] ↓M2 macrophages in murine lung [38] ↓ activated DCs in murine and human lung [39,40] Unchanged in murine lung [38] ↓ Th1 and Th17 in peripheral blood during the first week of life in BPD patients [41] ↓ Treg in cord blood in BPD patients [36] NEC ↓ M1 macrophages in murine NEC tissue [42] Unknown ↓ Th17 in human NEC tissue [35] ↓Treg in human NEC tissue [35] Periventricular leukomalacia (PVL), Hypoxic ischemic encephalopathy (HIE), Bronchopulmonary dysplasia (BPD), Necrotising enterocolitis (NEC), Lymphocytes T helper (Th), cerebrospinal fluid (CSF), Denditric cells (DCs), Hypoxia-ischemia (HI)…”

“…The incidence of HIE in developed countries is approximately 1 to 3 per 1,000 live births, and is responsible for approximately 30 % of the cases of cerebral palsy in childhood [88]. The intrapartum hypoxic ischemic insult initiates an energy depletion with subsequent reperfusion-induced cell death cascades [37]. In experimental HIE, the inflammatory response to hypoxic ischemic injury caused an increased influx of neutrophils to the brain [37].…”

“…The intrapartum hypoxic ischemic insult initiates an energy depletion with subsequent reperfusion-induced cell death cascades [37]. In experimental HIE, the inflammatory response to hypoxic ischemic injury caused an increased influx of neutrophils to the brain [37]. Microglia, the brain resident macrophages which can either have a pro-inflammatory phenotype (M1) or promote tissue repair and suppress inflammation (M2) [89], are polarized towards an M1 phenotype after hypoxic ischemic injury [89] ( Table 1).…”