SLEEP MEDICINE


MELATONIN AND NOCTURNAL ASTHMA by Regina Patrick, RPSGT


A


sthmatics have long noted that symptom severity varies daily and seasonally. Recent studies showing a connection between mela-


tonin production and symptoms validate this observation. Asthma worsens at night when the daily production of melatonin is at its high- est and improves during the day when melatonin levels fall. Season- ally, asthma is worst during the dark days of winter when melatonin production is high but improves with the long sunny days of summer when melatonin production is low. Whether melatonin exacerbates symptoms directly or indirectly is unclear. Based on their results from a study at the National Jewish Med-


ical and Research Center in Denver, Colorado, E. Rand Sutherland et al proposes that melatonin may worsen symptoms by stimulating mononuclear cells to produce interleukins which cause tissue to become inflamed during an allergic response. When interleukins act on airway tissue, the resultant inflammation causes the symp- toms of asthma. Interleukin production is higher in asthmatics than in people


without the disorder. Production fluctuates throughout the day being higher at night then falling during the day. Yet not all asthmatics have worsening symptoms at night. To understand if differences in sensitivity to melatonin could explain this, Sutherland used three groups of subjects in their study: subjects with nocturnal asthma; subjects with non-nocturnal asthma (i.e., subjects with asthma whose symptoms do not worsen at night); and subjects who did not have asthma. The subjects’ blood was drawn in early morning and early


evening. Mononuclear cells were isolated and subjected to 3 in vitro conditions for each subject. For the first condition, cells were mixed with stimulants to promote cell growth (and therefore interleukin production). For the second condition, cells were mixed with a so- lution containing the stimulants and melatonin. For the third condi- tion, cells were not mixed with either stimulants or melatonin. The stimulants/melatonin solution caused interleukin levels to


increase significantly in all three subject groups compared to when cells were exposed to stimulants alone. Subjects with nocturnal asthma had the highest increase in interleukin levels at early evening. This was as expected since nocturnal asthmatics begin to have symptoms by early evening. Non-nocturnal asthmatic subjects had significantly less increase in interleukin production and the con- trols had the least increase. This trend changed dramatically by the time early morning samples were taken 12 hours later. By then, non- nocturnal asthmatic subjects’ interleukin levels had increased by 104.5% from the 4:00 p.m. reading while the nocturnal asthmatic subjects’ levels had risen only slightly (by 3.1%) from the 4:00 p.m. reading. Sutherland proposes several theories for this: 1. Mononuclear cells of nocturnal asthma subjects, already highly activated, became unable to respond further to the stimulatory ef- fects of melatonin. 2. Slight variations in the cell receptors of nocturnal and non-


nocturnal asthmatics may result in different responses to mela- tonin. 3. Mononuclear cells - being from blood rather than secretions may not be accurately reflecting airway inflammation. 4. Mononuclear cells in nocturnal asthmatics, as a result of the allergic response, may have migrated into the lungs from the blood leaving less cells (and therefore less interleukin levels) present in the subjects’ blood samples. 5. The results may only be an in vitro finding; an in vivo study may have given the expected results. Despite the surprising early morning results, the fact that a


much greater increase in interleukin production occurred when melatonin was added to the stimulants suggests that melatonin is playing a major role in airway inflammation in asthmatics. In the melatonin/stimulant solution, Sutherland used various


concentrations of melatonin to test whether interleukin production would increase as the level of melatonin increased. The concen- tration ranged from 10-12 molar to 10-5 molar. In all three groups, although the interleukin level was heightened, the rate of produc- tion did not increase as concentrations of melatonin increased. From this, they concluded that even small amounts of melatonin could cause problematic inflammation for people with nocturnal asthma. E. V. Evsyukova tracked circadian changes in a melatonin


metabolite found in the urine of aspirin-sensitive asthmatic sub- jects, non-aspirin-sensitive asthmatic subjects, and controls (non- asthmatics). He found that melatonin levels are lower in asthmatics and believes this low level of melatonin can lead to symptoms, particularly in aspirin-sensitive asthmatics. At night, the control subjects had the highest level of the mela-


tonin metabolite. In the daytime, the level of melatonin metabolite fell dramatically in aspirin-sensitve asthmatics and was the lowest of the 3 groups. The non-aspirin asthmatics had the highest daytime level but this level was the same as the night level. Evsyukova sus- pected that low levels of melatonin may impair platelet function by making the platelets more sensitive to melatonin and substances which are similar to melatonin such as aspirin. He found that in- creasing the concentrations of melatonin led to increasing platelet clumping signifying an increasing allergic response. This allergic response to melatonin and similar substances causes the platelets to produce increased amounts of leukotrienes, a group of sub- stances which causes tissue inflammation, leading to symptoms of asthma. In recent years, scientists noted that melatonin enhances mi-


gration of mononuclear cells and other types of white blood cells from the bone marrow into the blood and then on to the site of an antigen during an allergic response. Eivor Martins et al., found that cell migration does not occur in rats that have undergone removal of the pineal gland which virtually stops


Focus Journal Fall 2011 5 continued on page 15


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30