Oxygen therapy given newborns with persistent pulmonary hypertension likely works to cement the molecular changes that led to the condition in the first place, further worsening, rather than treating, the illness.
The study, “Hypoxia and hyperoxia potentiate PAF receptor-mediated effects in newborn ovine pulmonary arterial smooth muscle cells: significance in oxygen therapy of PPHN“, published in the journal Physiological Reports, explored how molecular signaling events contribute to preparing the newborn’s lungs for breathing, and found that when these signaling events fail, lung hypertension follows.
When a child is born and brought into the oxygen-rich environment of our atmosphere, the lungs, inactive until that time, go through extensive changes. Lung arteries that are compressed in the fetus undergo in a newborn a series of molecular signals to make sure they dilate, and effectively transfer oxygen from the lungs into the blood.
Scientists well know the factors involved in this process, but not the details of how they might contribute to the disease.
Researchers have long suspected that a factor termed PAF (platelet activating factor) is involved in mediating the molecular changes leading to lung hypertension. PAF levels are high in sheep lung vessels before birth, and drop once the animal starts breathing. But if the newborn animal is exposed to low oxygen levels for a longer time, PAF increases again.
A common way of treating pulmonary hypertension in newborn babies is oxygen treatment, allowing them to breathe pure oxygen. This is intended to overcome the low-oxygen environment caused by the lung dysfunction.
Lately, however, reports that this practice might actually damage the lungs have emerged. A research team at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, in California, decided to study the molecular changes that accompany lung transformation upon birth.
The team isolated smooth muscle cells — a crucial component of blood vessel walls known to act abnormally in lung hypertension — and studied the cells in the lab. Comparing cells isolated from lung arteries of both unborn and newborn sheep, the researchers measured levels of molecules involved in constricting and dilating blood vessels, tracking how environments with low or high oxygen levels affected those levels.
They discovered that prostacyclin — a molecule having a dilating effect on blood vessels — increased upon birth, and rose higher still in a low-oxygen environment. In contrast, cells grown in a high-oxygen environment produced 46 percent less of prostacyclin, effectively counteracting processes necessary to the development of newborn lungs.
Blocking PAF increased the levels of this vessel-dilating molecule when oxygen levels were normal or low, but in a high-oxygen environment, blocking PAF had the reverse effect and lowered prostacyclin levels.
The team also found that low oxygen levels increased PAF signaling, and both high and low oxygen levels increased the growth and multiplication of smooth muscle cells in a manner that depended on PAF signaling, suggesting that the involvement of PAF in infant lung hypertension is complex and dependent on the surrounding oxygen levels.
A vessel constricting factor called thromboxane A2 was also seen to decrease upon birth. But thromboxane A2 was not affected by changes in available oxygen, suggesting that promoting blood vessel dilation is more important than blocking vessel constriction in an infant’s lungs.
Findings clearly demonstrated the deleterious effect oxygen treatment can have on infant lungs, possibly leading to changes that contribute to the irreversible remodeling of lung blood vessels and, ultimately, pulmonary hypertension.
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