RESUMOA melatonina é um hormônio produzido pela glândula pineal, cuja secreção está diretamente relacionada ao ciclo claroescuro. É um poderoso antioxidante e tem papel fundamental na regulação do estado sono/vigília, do ritmo de vários processos fisiológicos, participando do controle do relógio biológico, inclusive nos seres humanos. Ressalta-se que há evidências da sua ação no sistema genital feminino, influenciando a função ovariana e a fertilidade. De fato, este hormônio interage com esteróides sexuais, como o estrogênio, modificando a sinalização celular e a resposta no tecido alvo. Estudos clínicos sugerem que o tratamento com a melatonina interviria com a evolução de neoplasia-dependente do estrogênio. O objetivo dessa revisão é analisar as principais ações da melatonina no sistema neuroendócrino, no ciclo sono-vigília, no sistema imunológico, no sistema cardiovascular, bem como no sistema reprodutor. UNITERMOS INTRODUÇÃOA melatonina é uma indolamina produzida pela glândula pineal, que está localizada no teto do terceiro ventrículo entre os dois hemisférios cerebrais. Pesa aproximadamente 0,13 gramas e possui aproximadamente 1,2 cm de diâmetro, originando-se do diencéfalo. É órgão endócrino ativo, conectado à retina pelas projeções retino-hipotalâmicas via núcleo supraquiasmático do hipotálamo, no qual funciona como um controle autônomo para o gânglio cervical superior, de onde as fibras ganglionares posteriores alcançam finalmente a pineal 1 . Há outras fontes produtoras deste hormônio como a retina, corpo ciliar da íris, glândulas harderianas e lacrimais, linfócitos, intestino grosso e em menor quantidade em outros locais 2,3,4 . Essas outras fontes teriam contribuição mínima para a concentração plasmática da melatonina, porém, seriam importantes para ação local na qual foram produzidas. Essa produção extrapineal justificaria a presença de baixos níveis de 6-sulfatoximelatonina (seu principal metabólito) na urina de ratas que passaram por remoção da glândula pineal 2,3,4 . Salienta-se que o ritmo circadiano e a grande concentração noturna desse hormônio são determinados pela síntese deste hormônio na pineal 2,3,4 . Papel funcional da melatonina na regulação da ritmicidade biológicaA glândula pineal, associadamente aos núcleos supraquiasmáticos hipotalâmicos, constitui parte importante do sistema neuroendócrino, responsável pela organização temporal dos diversos eventos fisiológi-cos e comportamentais 5 . Isso é fundamental para a adaptação do indivíduo e da espécie às flutuações temporais cíclicas do meio ambiente (regulação endócrina e metabólica); regulação do ciclo sono-vigília; regulação do sistema imunológico; regulação cardiovascular, em especial da pressão arterial, bem como no sistema genital 2,34,6,7 . Além disso, a melatonina influencia o ritmo de vários outros processos fisiológicos durante a noite: a digestão torna-se mais lenta, a temperatura corporal cai, o ritmo cardíaco e a pressão sangüínea diminuem e o sistema imunológico é estimulado. Parece ser capaz de aumentar a mobilidade e a ati...

Abstract. Our aim was to evaluate the pulmonary changes induced by Leptospira interrogans infection in hamsters, and the gene expression of endogenous mediators in lung fragments during 28 days of observation. The animals were euthanized on days 4, 7, 14, 21, and 28 post-inoculation. Histopathologic lung analysis showed hemorrhage, pneumonia, alveolar congestion, and infiltrated cellular areas, with increasing severity until day 21 post-inoculation. Tumor necrosis factor (TNF)-a mRNA expression enhanced in first days with peak on day 4 and slightly decreased in the final phase. The interleukin (IL)-10 remained relatively constant throughout the period, with the exceptions of days 4 and 14. The endothelial nitric-oxide synthesis (eNOS) showed an increased expression on day 4, followed by an augment on days 7 and 14, and remaining constant up to day 28 post-infection. Our results demonstrate that inoculation of L. interrogans sorovar Icterohaemorrhagiae induced pulmonary lesions, including pulmonary hemorrhage, supporting that the lung is a target organ.

Tumor necrosis factor-alpha (TNF-α) is one of the most important proinflammatory cytokines which plays a central role in host defense and in the acute inflammatory response related to tissue injury. The major source of TNF-α are immune cells such as neutrophils and macrophages. We tested the hypothesis that pentoxifylline, a methylxanthine derivative, down-regulates proinflammatory cytokine expression during acute lung injury in rats. Male Wistar rats weighing 250 to 450 g were anesthetized ip with 50 mg/kg sodium thiopental and randomly divided into three groups: group 1 (N = 7): tidal volume (V T ) = 7 ml/kg, respiratory rate (RR) = 50 breaths/min and normal saline infusion; group 2 (N = 7): V T = 42 ml/kg, RR = 9 breaths/min and normal saline infusion; group 3 (N = 7): V T = 42 ml/kg, RR = 9 breaths/min and pentoxifylline infusion. The animals were ventilated with an inspired oxygen fraction of 1.0, a positive end-expiratory pressure of 3 cmH 2 O, and normal saline or pentoxifylline injected into the left femoral vein. The mRNA of TNF-α rapidly increased in the lung tissue within 180 min of ventilation with a higher V T with normal saline infusion. The concentrations of inflammatory mediators were decreased in plasma and bronchoalveolar lavage (BAL) in the presence of higher V T with pentoxifylline infusion (TNF-α: plasma, 102.2 ± 90.9 and BAL, 118.2 ± 82.1; IL-1ß: plasma, 45.2 ± 42.7 and BAL, 50.2 ± 34.9, P < 0.05). We conclude that TNF-α produced by neutrophil influx may function as an alert signal in host defense to induce production of other inflammatory mediators.

PURPOSE: To investigate the protective effect of pentoxifylline against the lung injury observed after intestinal ischemia (I) followed by a period of reperfusion (R). METHODS: Twenty-eight male Wistar rats were equally divided into 4 experimental groups and operated under ketamine-xylazine anesthesia. (1) Sham: falsely-operated animals; (2) SS+IR: intestinal ischemia was accomplished by clipping the superior mesenteric artery during 60 minutes, with an administration of a standard volume of saline solution (SS) 5 min before the end of the ischemia period; the clip was then releases or a 120-min period of reperfusion; (3) I+PTX+R: ischemia as above, PTX was administered (25 mg/kg) and the gut reperfused as above; (4) PTX+I+PTX+R: Five minutes before arterial occlusion PTX was administered; the superior mesenteric artery was then clipped for 60 minutes. After 55-min ischemia, an additional dosis of PTX was administered; the clip was removed for reperfusion as above. At the 60th min of reperfusion a third dosis of PTX was administered. RESULTS: PTX markedly attenuated lung injury as manifested by significant decreases (all P<0.001 as compared with the SS+IR group) of pulmonary wet/dry tissue weight ratio, total protein content, myeloperoxidase activity and tumor necrosis factor-alpha. Moreover, it was apparent that in the group PTX+I+PTX+R the improvements have been even more significant. CONCLUSION: PTX exerted a protective effect on the lung from the injuries caused by intestinal ischemia/reperfusion.

Although assist ventilation with FIO2 0.21 is the preferable mode of ventilation in the intensive care unit, sometimes controlled ventilation with hyperoxia is needed. But the impact of this setting has not been extensively studied in elderly subjects. We hypothesized that a high fraction of inspired oxygen (FiO(2)) and controlled mechanical ventilation (CMV) is associated with greater deleterious effects in old compared to adult subjects. Adult and old rats were submitted to CMV with low tidal volume (6 ml/kg) and FiO(2) 1 during 3 or 6 h. Arterial blood gas samples were measured at 0, 60 and 180 min (four groups: old and adult rats, 3 or 6 h of CMV), and additionally at 360 min (two groups: old and adult rats, 6 h of CMV). Furthermore, total protein content (TPC) and tumor necrosis factor-alpha (TNF-α) in bronchoalveolar lavage were assessed; lung tissue was used for malondialdehyde and histological analyses, and the diaphragm for measurement of contractile function. Arterial blood gas analysis showed an initial (60 min) greater PaO(2) in elderly versus adult animals; after that time, elderly animals had lowers pH and PaO(2), and greater PaCO(2). After 3 h of CMV, TPC and TNF-α levels were higher in the old compared with the adult group (P < 0.05). After 6 h of MV, malondialdehyde was significantly higher in elderly compared with the adult animals (P < 0.05). Histological analysis showed leukocyte infiltration and edema, greater in old animals. In diaphragm, twitch contraction with caffeine significantly declined after 6 h of CMV only for the elderly group. These data support the hypothesis that relatively short-term CMV with low tidal volume and hyperoxia has greatest impact in elderly rats, decreasing diaphragmatic contractile function and increasing lung inflammation.

Experimental models of sepsis-induced pulmonary alterations are important for the study of pathogenesis and for potential intervention therapies. The objective of the present study was to characterize lung dysfunction (low PaO 2 and high PaCO 2 , and increased cellular infiltration, protein extravasation, and malondialdehyde (MDA) production assessed in bronchoalveolar lavage) in a sepsis model consisting of intraperitoneal (ip) injection of Escherichia coli and the protective effects of pentoxifylline (PTX). Male Wistar rats (weighing between 270 and 350 g) were injected ip with 10 7 or 10 9 CFU/100 g body weight or saline and samples were collected 2, 6, 12, and 24 h later (N = 5 each group). PaO 2 , PaCO 2 and pH were measured in blood, and cellular influx, protein extravasation and MDA concentration were measured in bronchoalveolar lavage. In a second set of experiments either PTX or saline was administered 1 h prior to E. coli ip injection (N = 5 each group) and the animals were observed for 6 h. Injection of 10 7 or 10 9 CFU/100 g body weight of E. coli induced acidosis, hypoxemia, and hypercapnia. An increased (P < 0.05) cell influx was observed in bronchoalveolar lavage, with a predominance of neutrophils. Total protein and MDA concentrations were also higher (P < 0.05) in the septic groups compared to control. A higher tumor necrosis factor-alpha (P < 0.05) concentration was also found in these animals. Changes in all parameters were more pronounced with the higher bacterial inoculum. PTX administered prior to sepsis reduced (P < 0.05) most functional alterations. These data show that an E. coli ip inoculum is a good model for the induction of lung dysfunction in sepsis, and suitable for studies of therapeutic interventions. Correspondence

Mechanical ventilation with high tidal volumes (V T ) has been shown to induce lung injury. We examined the hypothesis that this procedure induces lung injury with inflammatory features. Anesthetized male Wistar rats were randomized into three groups: group 1 (N = 12): V T = 7 ml/kg, respiratory rate (RR) = 50 breaths/min; group 2 (N = 10): V T = 21 ml/kg, RR = 16 breaths/min; group 3 (N = 11): V T = 42 ml/kg, RR = 8 breaths/min. The animals were ventilated with fraction of inspired oxygen of 1 and positive end-expiratory pressure of 2 cmH 2 O. After 4 h of ventilation, group 3, compared to groups 1 and 2, had lower PaO 2 [280 (range 73-458) vs 517 (range 307-596), and 547 mmHg (range 330-662), respectively, P<0.05], higher wet lung weight [3.62 ± 0.91 vs 1.69 ± 0.48 and 1.44 ± 0.20 g, respectively, P<0.05], and higher wet lung weight/dry lung weight ratio [18.14 (range 11.55-26.31) vs 7.80 (range 4.79-12.18), and 6.34 (range 5.92-7.04), respectively, P<0.05]. Total cell and neutrophil counts were higher in group 3 compared to groups 1 and 2 (P<0.05), as were baseline TNF-α concentrations [134 (range <10-386) vs 16 (range <10-24), and 17 pg/ml (range <10-23), respectively, P<0.05]. Serum TNF-α concentrations reached a higher level in group 3, but without statistical significance. These results suggest that mechanical ventilation with high V T induces lung injury with inflammatory characteristics. This ventilatory strategy can affect the release of TNF-α in the lungs and can reach the systemic circulation, a finding that may have relevance for the development of a systemic inflammatory response.

Oliveira-Júnior IS de, Maganhin CC, Carbonel AAF, Monteiro CMR, Cavassani SS, Oliveira-Filho RM. Effects of pentoxifylline on tnf-alpha and lung histophatology in hcl-induced lung injury. Clinics. 2008;63(1):77-84. OBJECTIVE:To evaluate the effects of pentoxifylline on hydrochloric acid-induced lung lesions in rats subjected to mechanical ventilation. METHODS: Twenty male, adult Wistar-EPM-1 rats were anesthetized and randomly grouped (n=5 animals per group) as follows: control-MV (mechanical ventilation, MV group); bilateral instillation of HCl (HCl group); bilateral instillation of HCl followed by pentoxifylline (50 mg/kg bw) infusion (HCl+PTX group) and pentoxifylline infusion followed by bilateral instillation of HCl (PTX+HCl group). At 20, 30, 90 and 180 min after treatments, the blood partial pressures of CO 2 and O 2 were measured. The animals were euthanized, and bronchoalveolar lavages were taken to determine the contents of total proteins, corticosteroid and TNF-α. Samples of lung tissue were used for histomorphometric studies and determining the wet-to-dry (W/D) lung weight ratio. RESULTS: In the MV group, rats had alveolar septal congestion, and, in the HCl group, a remarkable recruitment of neutrophils and macrophages into the alveoli was noticed; these events were reduced in the animals with PTX+HCl. The partial pressure of oxygen increased in PTX+HCl animals (121±5 mmHg) as compared with the HCl (62±6 mmHg) and HCl+PTX (67±3 mmHg) groups within 30 minutes. TNF-α levels in bronchoalveolar lavage were significantly higher in the HCl group (458±50 pg/mL), reduced in the HCl+PTX group (329±45 pg/mL) and lowest in the PTX+HCl group (229±41 pg/mL). The levels of corticosteroid in bronchoalveolar lavage were significantly lower in the HCl (8±1.3 ng/mL) and HCl+PTX group (16±2 ng/mL) and were highest in the PTX+HCl (27±1.9 ng/mL). CONCLUSION: Pretreatment with PTX improves oxygenation, reduces TNF-α concentration and increases the concentration of corticosteroid in bronchoalveolar lavage upon lung lesion induced by HCl.