How lung injury and therapeutic oxygen could alter white matter development

Abstract

Developmental brain injury describes a spectrum of neurological pathologies resulting from either antenatal or perinatal injury. This includes both cognitive and motor defects that affect patients for their entire lives. Developmental brain injury can be caused by a spectrum of conditions including stroke, perinatal hypoxia-ischemia, and intracranial hemorrhage. Additional risk factors have been identified including very low birth weight, mechanical ventilation, and oxygen (O₂ ) supplementation. In fact, infants with bronchopulmonary dysplasia, an inflammatory disease associated with disrupted lung development, have been shown to have decreased cerebral white matter and decreased intracranial volumes. Thus, there appears to be a developmental link between the lung, O₂ , and the brain that leads to proper myelination. Here, we will discuss what is currently known about the link between O₂ and myelination and how scientists are exploring mechanisms through which supplemental O₂ and/or lung injury can affect brain development. Consideration of a link between the diseased lung and developing brain will allow clinicians to fine tune their approaches in managing preterm lung disease in order to optimize brain health.

Keywords: White matter Injury; animal models; neurodevelopmental impairment; oxygen; prematurity.

Figure 1:. Mechanisms of NDI caused by antenatal or perinatal injury.

Schematic showing the relationship between various antenatal and perinatal conditions (top square) and NDI (bottom square). The square on the left indicates levels of oxygen that can cause CNS injury leading to NDI. The box on the left indicates how the immune system can contribute to CNS injury leading to NDI.

Figure 2:. The effects of oxygen exposure on oligodendroglial cells.

The top line of the figure indicates that cultured cells have been tested at ranges from physiological (1–5% O₂) to hyperoxic (80% O₂). In vivo studies lie somewhere in between, as it is not known what O₂ tensions exist in tissues of mice reared in high oxygen (75–85% O₂). The triangle with the blue to red gradient represents the O₂ gradient. Below this is the summary of the findings of the cell culture studies under hypoxia, room air and hyperoxia. Below this, positioned between room air and 80% O₂ is the summary of in vivo studies.

Figure 3:. Interaction of blood and the CNS in response to BPD

A schematic drawing of possible effects of BPD on the BBB and oligodendroglial differentiation. The blood vessel is placed above and below the CNS parenchyma. Basement membranes (BM) are indicated above right. Hyperoxia and inflammation associated with BPD may activate monocytes which accumulate and weaken the BBB by an unknown mechanism. This could allow blood proteins such as fibrinogen to penetrate the CNS parenchyma. This could activate BMP signaling through the ACVR1/BMPR2 receptor and either arrest OPC differentiation or trigger OPCs to differentiate into astrocytes, as has been observed in vitro. Monocytes bind to activated endothelium more efficiently and could enter the CNS parenchyma through diapedesis. These cells, as well as microglia could also respond to fibrinogen via Mac-1 and this increases their production of cytokines such as IL1β. Monocytes, monocyte-derived macrophages and microglia also produce reactive O₂ species (ROS) in response to hyperoxia that can cause axonal damage.