The Evolving Landscape of Neuroinflammation After Neonatal Hypoxia-Ischemia
Hypoxic-ischemic brain injury remains a leading cause of mortality and morbidity in neonates. The inflammatory response, which is characterized in part by activation of local immune cells, has been implicated as a core component for the progression of dam
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Abstract Hypoxic-ischemic brain injury remains a leading cause of mortality and morbidity in neonates. The inflammatory response, which is characterized in part by activation of local immune cells, has been implicated as a core component for the progression of damage to the immature brain following hypoxia-ischemia (HI). However, mounting evidence implicates circulating immune cells recruited to the site of damage as orchestrators of neuron-glial interactions and perpetuators of secondary brain injury. This suggests that redirecting our attention from the local inflammatory response toward the molecular mediators believed to link brainimmune cell interactions may be a more effective approach to mitigating the inflammatory sequelae of perinatal HI. In this review, we focus our attention on cyclooxygenase-2, a mediator by which peripheral immune cells may modulate signaling pathways in the brain that lead to a worsened outcome. Additionally, we present an overview of emerging therapeutic modalities that target mechanisms of neuroinflammation in the hypoxic-ischemic neonate.
N. Fathali Department of Human Pathology and Anatomy, Loma Linda University, School of Medicine, Loma Linda, CA, USA N.H. Khatibi Department of Anesthesiology, Loma Linda University, School of Medicine, Loma Linda, CA, USA R.P. Ostrowski Department of Physiology, Loma Linda University, School of Medicine, Loma Linda, CA, USA J.H. Zhang (*) Department of Anesthesiology, Loma Linda University, School of Medicine, Loma Linda, CA, USA and Department of Physiology, Loma Linda University, School of Medicine, Loma Linda, CA, USA and Department of Neurosurgery, Loma Linda University, School of Medicine, 11234 Anderson Street, Room 2562B, Loma Linda, CA, USA e-mail: [email protected]
Keywords Hypoxia-ischemia · Neuroinflammation · Cyclo oxygenase-2 · Immature brain · Neuron-glial · Immune cell
Introduction Hypoxia-ischemia (HI) occurs in 1 to 6 per 1,000 live fullterm births [1]. Of those affected, 15–20% will die in the postnatal period, and 25% of survivors will be left with longterm neurological disabilities [2–4]. Intrauterine asphyxia is the underlying mechanism of hypoxic injury and is a consequence of circulatory problems, including clotting of placental arteries and placental abruption [5]. HI in the neonate is a manifestation of systemic hypoxia combined with reduced cardiac output [6]. Studies have shown that the pathophysiology of brain injury secondary to HI consists of a biphasic profile (Fig. 1). The initial phase of HI is characterized by brain acidosis and the depletion of high-energy phosphorylated compounds, such as adenosine triphosphate and phosphocreatine [1, 7, 8]. This primary energy failure leads to the loss of membrane ionic homeostasis, depolarization of the cell, osmotic dysregulation, and inhibition of protein synthesis, further leading to necrosis [9, 10]. The secondary processes evolve over days after the brain insult and are also characterized by a depletion of high-energy phosphorylated compounds, however withou
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