The control of breathing is essential for life. Without an adequate response to increased carbon dioxide levels, people can suffer from breathing disturbances, sickness, and panic; in worst-case scenarios, it can lead to premature death, as in sudden infant death syndrome. To counteract these events there has been some debate over how the brain controls breathing. Now, a study from researchers at the Karolinska Institutet shows how the brain controls a person’s breathing in response to changing oxygen and carbon dioxide levels in the blood. The team state that their findings shows when exposed to decreased oxygen or increased carbon dioxide levels, the brain releases a small molecule called Prostaglandin E2 (PGE2) to help protect itself and regulate breathing. The opensource study is published in the journal eLife.
Previous studies show that neural networks in the parafacial respiratory group/retrotrapezoid nucleus and the preBötzinger complex are important networks implicated in the central control of breathing. In addition, a CO2 sensitivity of astrocytes also mediates a vesicular-independent ATP release. Inflammation reduces the CO2 response and, particularly in neonatal mammals, can induce sighs, an altered response to hypoxia and potentially life-threatening apnea episodes as shown in humans, sheep, piglets and rodents. In the inflammatory pathway, prostaglandin E2 (PGE2) is an important molecular mediator, that together with its main receptor, the EP3R, play a role in the response to oxygen deprivation and elevated CO2 levels in the blood. Therefore, the lab hypothesized that both PGE2 and EP3R constitute parts of the respiratory machinery. The current study identifies a novel pathway linking the inflammatory and respiratory systems, with the ability to autoresuscitate when breathing fails.
The current study grew a section of a mouse’s brainstem in a type of dish to show this mechanism. The slice contained an arrangement of nerve and supporting cells that allowed it to ‘breathe’ for three weeks. During this time, the group monitored the cells and their behaviour in response to changes in the environment where this novel brainstem culture first revealed that cells responsible for breathing operate in a small-world network. Results show that groups of these cells work very closely with each other, with each group interconnected by a few additional cells that appear to work as hubs. Data findings show that this networking activity and the rhythmic respiratory motor output it generated were preserved for the full three weeks, suggesting that the brainstem can be used for long-term studies of respiratory neural network activity.
Results show that exposure to different substances made the brainstem breathe faster or slower. The team state that perhaps most interesting was its response to carbon dioxide, which triggered a release of PGE2. They go on to add that PGE2 acted as a signaling molecule that increased breathing activity in the carbon dioxide-sensitive brainstem region, leading to slower and deeper breaths, or ‘sighs’.
Data findings show that the study also reveals a novel pathway linking the inflammatory and respiratory systems. The team explain that PGE2 is released during inflammation and fever, which can dysregulate breathing patterns and interfere with normal responses to carbon dioxide, this can in turn cause disturbed and even dangerous halts in breathing. The lab state that these new insights have important implications for babies, who experience significantly reduced levels of oxygen during birth; at this stage, PGE2 protects the brain and prepares the brainstem to generate deep sigh-like breath intakes, resulting in the first breaths of air following birth.
The team surmise that their findings go some way to explaining how and why the human breathing responses to imbalanced oxygen and carbon dioxide levels are impaired during infectious episodes. They go on to add that it also helps further their understanding of why infection can inhibit breathing so severely in new-born babies. For the future, the researchers state that they now want to find out how breaths form and develop during episodes of inflammation. They conclude that this could be useful for researching potential new ways to save babies’ lives when they are unable to catch their breaths.
Source: Karolinska Institutet
