Perinatal Hyperoxia and Developmental Consequences on the Lung-Brain Axis

Figure 2

Hyperoxia-induced morphological changes and inflammatory responses in the developing brain and lung. Hyperoxia disrupts alveolar and vascular development in the immature lung resulting in fewer and larger alveoli and decreased vessel density ((a) upper panel). With regard to mechanisms underlying impaired lung development, enhanced ROS production stimulates alveolar epithelial cells type II (AECII) to produce proinflammatory cytokines (IL6, IL-18, IL-1beta, TNF-alpha, etc.) resulting in infiltration of peripheral leukocytes (macrophages, neutrophils, monocytes, etc.) ((a) lower panel). Detrimental effects of proinflammatory cytokines were ascribed to activation and polarization of alveolar and peripheral macrophages into proinflammatory M1 macrophages, which not only accelerate proinflammatory cytokine production but also lead to degeneration of AECII cells and reduced developmental transition from AECII into AECI. These mechanisms may contribute to reduced formation of alveoli. In the developing brain, first evidences suggest that hyperoxia impairs vascularization, though this needs to be proven in future studies ((b) upper panel). Similarly to the lung, hyperoxia leads to increased oxidative stress through enhanced ROS production ((b) lower panel). Increased ROS have detrimental effects on oligodendrocyte maturation, myelination, and neuronal survival, leading to ultrastructural abnormalities of myelin formation and grey matter injury ((b) lower panel). Furthermore, increased ROS in the brain activate microglia cells, associated with proinflammatory cytokine expression (IL-18, IL-1beta, TNF-alpha, etc.), thereby additionally enhancing both white and grey matter injury. In contrast to hyperoxia-injured lungs, peripheral leukocytes do not infiltrate the brain, most likely due to protection by unique characteristics of the blood-brain barrier.