Circadian rhythm in experimental granulomatous inflammation is modulated by melatonin

Abstract

Biological rhythms are detected in a variety of physiological and pathological conditions in man and animals, such as rheumatoid arthritis and asthma. Here we describe a circadian rhythm in experimental infectious and non-infectious granuloma. After 30 days of BCG (Bacillus Calmette-Guerin) or nystatin inoculation in the left hind foot of C57B1/6 mice, there is an oscillation with a period of approximately 24 hr in the variation of paw thickness, indicating a circadian rhythm. The acrophase occurred during the light phase, between 9:00 and 13:00 hr, while the nadir occurred in the dark phase, between 21:00 and 01:00 hr. The vascular permeability around the granulomatous lesions was higher at 12:00 hr than at 24:00 hr. This is in agreement with the observation that the thickness of a paw with granulomatous lesion is larger during the light phase. This rhythmic variation was eliminated by either pinealectomy or superior cervical ganglionectomy, which greatly reduce melatonin levels in the blood. Nocturnal replacement of melatonin in pinealectomized mice led to the re-establishment of the circadian rhythm. Thus, the rhythm of the granulomatous lesion is due to the rhythmic melatonin release by the pineal gland. This approach opens new questions regarding the modulation of chronic inflammation in inflammatory diseases that present rhythmic symptoms throughout the day.

Bioinformatic Analysis of Circadian Gene Oscillation in Mouse Aorta

“…40 In the present studies, leakage of the Evans blue dye underwent a time-dependent variation in the mouse. Indeed, variation in genes relevant to barrier function may contribute not only to diurnal variation in edema accumulation 41,42 but also to the diurnal variation in severity of inflammatory syndromes, such as bronchial asthma 43 and arthritis. 44 Inclusion of genes relevant to vascular integrity and response to injury in the oscillating subset raise the possibility that the dysplastic response to injury, which contributes to restenosis after percutaneous angioplasty, might be conditioned by the timing of the procedure.…”

Melatonin inhibits nitric oxide production by microvascular endothelial cells in vivo and in vitro

“…Thus, bearing in mind that (a) endothelial-derived NO mediates neutrophil adherence (Schaefer et al, 1998); (b) L-NAME inhibits vascular permeability induced by vascular endothelial growth factor (Murohara et al, 1998); (c) caveolin-1 knockout mice exhibit an increased vascular permeability (Schubert et al, 2002); and (d) mesenteric and cremaster microvascular hypermeability is blunted in eNOS knockout mice (Hatakeyama et al, 2006), we could propose that eNOSderived NO is linked to the early steps of the inflammatory response and that melatonin would also regulate this function. We have already shown that low doses of melatonin inhibit paw oedema in a model of chronic inflammation in mice (Lopes et al, 1997) and vascular permeability induced by leukotriene B 4 (Lotufo et al, 2006).…”

“…Bradykinin, ATP and histamine are involved in mechanisms such as immune responses, inflammation and endothelial-mediated vasodilatation, with some of these actions being mediated by NO (Hill et al, 1997;Kunapuli and Daniel, 1998;Leeb-Lundberg et al, 2005;Burnstock, 2006). In addition, an immunomodulatory role of melatonin has been proposed (Lopes et al, 1997;Pontes et al, 2006). Thus, bearing in mind that (a) endothelial-derived NO mediates neutrophil adherence (Schaefer et al, 1998); (b) L-NAME inhibits vascular permeability induced by vascular endothelial growth factor (Murohara et al, 1998); (c) caveolin-1 knockout mice exhibit an increased vascular permeability (Schubert et al, 2002); and (d) mesenteric and cremaster microvascular hypermeability is blunted in eNOS knockout mice (Hatakeyama et al, 2006), we could propose that eNOSderived NO is linked to the early steps of the inflammatory response and that melatonin would also regulate this function.…”

Efeitos da melatonina no sistema genital feminino: breve revisão

“…Esta ritmicidade não é observada em camundongos pinealectomizados. O padrão do processo inflamatório é restaurado após reposição de melatonina, em doses farmacológicas, adicionada à água, oferecida apenas na fase de escuro 15,16 . Por outro lado, em inflamação alérgica pulmonar, asma brônquica, a melatonina apresenta efeito pró-inflamatório 17 .…”