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Interrupted nights

Inflammation temporarily blocks production of the hormone that tells the body that it's time to sleep

nasaDoctors and nurses are used to the  havoc that a stay, even a short one, in intensive care units brings to  patients’ lives. During recovery from acute pneumonia or from surgery, patients sleep beyond the normal number of hours during the day, or they suffer from insomnia at night and get hungry at unusual hours. This is not the only issue. The body temperature, the heartbeats and hormone production fluctuate at a pace that differs from the 24-hour cycle that regulates the lives of human beings and of animals, as if an inner clock had stopped functioning properly. Until very recently, the common belief was that the lack of synchronization between the bodily functions and the outside world were a consequence of the artificial lighting found at intensive care centers. This is one of the reasons why at one time there was a proposal to install windows in these rooms, so that patients could perceive daytime and nighttime. But this strategy proved to be inefficient and now we know why.

Experiments conducted by the team headed by pharmacologist Regina Pekelmann Markus, from the University of São Paulo (USP), indicate that the cause of this lack of synchronization is not the fact that it is impossible to distinguish whether it’s day or night outside. The origin of this imbalance seems to be the inflammation itself, provoked by an infection agent or by a surgical lesion, which temporarily interrupts the production of the hormone melatonin. Produced by the pineal gland, located at the base of the cerebrum, this hormone is a kind of molecular “Father Time” that adjusts the hands of the biological clock to  daytime and nighttime periods, telling the body whether it is day or night, winter or summer.

When the sun sets and the quantity of light that reaches the eyes diminishes, the cells of the retina send an order to the pineal gland to increase the production of melatonin; this production grows until early dawn. As soon as it is produced – always in extremely low doses, which in human beings amount to some 150 picograms per milliliter of blood – the melatonin flows into the bloodstream and spreads throughout the body. “This is the sign for the cells to get ready to carry out the tasks they normally carry out at night,” Regina explains. In humans and other beings with daytime habits, the increase of melatonin in the bloodstream slows down the body’s pace and prepares it for sleep: the body temperature falls, the heart starts beating more slowly and the filtering of blood by the kidneys slows down. Rodents with night habits go through exactly the opposite cycle and the melatonin prepares their bodies for other essential life activities, such as the search for food and reproduction.

Regina did not verify the effect of inflammation on melatonin levels overnight. It took her ten years of work – and a number of experiments with mice, rats and human beings – to put together the pieces of this complicated biochemical jigsaw puzzle that had been presented to her in 1995 by Cristiane Lopes, one of her doctoral students. Cristiane was interested in discovering whether the level of inflammation varied at a specific rate during the day and in conjunction with other bodily functions, such as hormone production, blood pressure levels or digestion.

Regina and Cristiane planned to conduct a test that simulated chronic inflammation in mice every 24 hours. One month after injecting tuberculosis bacilli into the rodents’ paws, Cristiane started to measure the swelling and the level of vascular permeability – some of the parameters that define inflammation and facilitate the arrival of defense cells to the lesion -, every four hours for two days. Result: the inflammation was less intense at night, the period during which the concentration of melatonin in the blood is high. The anti-inflammatory properties of melatonin are already well known. This variation disappeared when Cristiane and Regina surgically extracted the mice’s pineal gland. The variation was seen again when they started giving the mice hormones, as was reported in an article published in the Journal of Pineal Research in 1997. This was the first sign that inflammation also followed melatonin cycles, whose production fluctuates throughout 24-hour periods.

The next step was to find out whether the effect was determined exclusively by the melatonin, given that the level of the corticosterone hormone also varies during the day. Corticosterone, produced by the suprarenal gland, is another powerful anti-inflammatory agent. Cristiane and Regina submitted the mice with chronic inflammation to two kinds of surgery. They extracted the pineal gland from a group of rodents and, as expected, the inflammation became as intense during the day as at night. Without the pineal gland, the mice did not produce melatonin, but they still produced corticosterone. Another group of mice was submitted to the extraction of the suprarenal gland, located above the kidneys. This group also showed no variation in the intensity of the inflammation during a 24-hour period. Both the swelling and the vascular permeability, however, diminished later on at night, when both groups of animals were treated with melatonin.

“In addition to indicating that the hormone produced by the suprarenal gland also influenced the intensity of the inflammation,” says Regina, “this result also suggested that the corticosterone was regulating the production of melatonin.” This reasoning is less complicated than it seems. If the main anti-inflammatory effects were produced by the corticosterone, the mice that underwent pineal gland extraction – and therefore would not have produced melatonin – should have had less intense inflammation at night, which did not occur. The complement to this response came from tests on rodents whose production of corticosterone was interrupted by the extraction of the suprarenal glands. Those mice did not produce melatonin at night, even though their pineal glands had remained intact, as Cristiane and Regina described in an article published in 2001 in Inflammation Research. The absence of corticosterone production was the only factor that could have had an influence in this case.

It was clear that as the production cycle of the pineal gland hormones and of the suprarenal gland hormones modified the body’s response to inflammation, the effect would help understand why someone who has a deep cut or catches the flu perceives that the symptoms worsen during the day and improve at night. But it was still necessary to discover how the order to produce melatonin occurred at the molecular level. In collaboration with Jamil Assreuy, from the Federal University of Santa Catarina, and Maria Christina Avellar, from the Federal University of São Paulo, Regina and physiologist Zulma da Silva Ferreira, from the University of São Paulo, cultivated the rats’ pineal glands in vitro. They verified that, at low concentrations of the kind observed during the day in those rodents and at night in human beings, the corticosterone activates the noradrenalin neurotransmitter and triggers a chemical cascade that leads to the production of melatonin. But in higher doses, similar to the ones found in intense inflammatory processes, the corticosterone blocks the activity of the pineal gland.

In milk
In another study, conducted together with pediatrician Magda Carneiro-Sampaio and immunologist Gerlândia Pontes, both from the University of São Paulo, Regina analyzed the concentration of melatonin in the milk of mothers who had recently given birth and had developed non-infectious mastitis, an inflammation that causes breast pain and tenderness. This condition is caused by the accumulation of milk in the breasts immediately after the woman gives birth. The measuring of hormones in the mothers´ milk twice a day – at midday and at midnight – showed that the concentration of melatonin in women with mastitis was consistently low, a sign that the pineal gland was not functioning properly. However, the level of melatonin in women who had not developed mastitis was consistently low during the day and high at night.

The blocking of melatonin production is associated with high levels, found in the mother’s milk, of a protein that the defense cells launch into the blood stream during an inflammation: the alpha tumor necrosis factor. This protein helps fight invading microorganisms – such as bacteria and fungi – where the inflammation is located, but ultimately de-activates the pineal gland, according to results presented at the end of last year in two articles published in the Journal of Pineal Research. From the organic point of view, this effect makes a lot of sense. The reduction in the activity of the pineal gland and the resulting reduction of the melatonin level, which acts as an anti-inflammatory agent, allow the defense cells to efficiently battle inflammation at night or during the day. “If it were produced in high systemic doses, it would stop the inflammation from progressing and would solve the problem,” says Regina.

Given that in acute inflammatory processes – such as mastitis or other more serious ones, which demand intensive care – the patient does not naturally produce melatonin at night, it stands to reason that it is useless to put in windows in intensive care centers, explains the pharmacologist. In 2003 and 2004, she was the head of the Bureau of Science and Technology of the Ministry of Science and Technology. After the acute phase of the inflammation subsides, the body recovers its normal pace and is able to once again make the distinction between day and night.