Itamar Souza de Oliveira-Júnior

Pentoxifylline decreases tumor necrosis factor and interleukin-1 during high tidal volume.

Tumor necrosis factor-alpha (TNF-alpha) 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-alpha 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 cmH2O, and normal saline or pentoxifylline injected into the left femoral vein. The mRNA of TNF-alpha 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-alpha: plasma, 102.2+/-90.9 and BAL, 118.2+/-82.1; IL-1 : plasma, 45.2+/-42.7 and BAL, 50.2+/-34.9, P < 0.05). We conclude that TNF-alpha produced by neutrophil influx may function as an alert signal in host defense to induce production of other inflammatory mediators.

Efeitos da melatonina no sistema genital feminino: breve revisão

Melatonin is secreted by the pineal gland and this is linked to the day/night cycle. It is an antioxidant and plays a fundamental role in the regulation of the jet-lag stage, in several physiological reactions and in control of the biologic rhythm. Human melatonin has an important influence on the female genital system. In fact, melatonin may influence production and action of steroids, modifying cellular signalization on the target tissue. There are many evidences that the melatonin therapy may be interfering with neoplasia development, mainly of the estrogen-dependent tumor. This paper aims to analyze the actions of melatonin on the neuroendocrine, immunological and cardiovascular systems, as well as on the reproductive function.

Ventilation with high tidal volume induces inflammatory lung injury

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 cmH2O. After 4 h of ventilation, group 3, compared to groups 1 and 2, had lower PaO2 [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-alpha concentrations [134 (range <10-386) vs 16 (range <10-24), and 17 pg/ml (range <10-23), respectively, P<0.05]. Serum TNF-alpha 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-alpha in the lungs and can reach the systemic circulation, a finding that may have relevance for the development of a systemic inflammatory response.

Pretreatment with pentoxifylline attenuates lung injury induced by intestinal ischemia/reperfusion in rats

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.

Effects of Pentoxifylline on TNF-Alpha and Lung Histopathology in HCl-Induced Lung Injury

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 CO2 and O2 were measured. The animals were euthanized, and bronchoalveolar lavages were taken to determine the contents of total proteins, corticosterone 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 corticosterone 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 corticosterone in bronchoalveolar lavage upon lung lesion induced by HCl.

Effect of pentoxifylline on lung inflammation and gas exchange in a sepsis-induced acute lung injury model

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 PaO2 and high PaCO2, 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). PaO2, PaCO2 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.

Effect of Ischemic Preconditioning on Injuries Caused by Ischemia and Reperfusion in Rat Intestine

To study whether ischemic preconditioning (IPC) attenuated intestinal dysfunction caused by ischemia (I) and reperfusion (R), rats were underwent 60 minutes of I which was produced by occlusion of the superior mesenteric artery, and/or 120 minutes R. The IPC group had the I procedure previously stimulated for 5 minutes and the R for 10 minutes. IPC and sham groups were injected with saline solution (SS) via the femoral vein 5 minutes before the I and R, and for R. After I or I/R, 2-cm jejunal segments were mounted in an organ bath to study neurogenic contractions stimulated by electrical pulses or KCl using a digital recording system. Thin jejunal slices were stained with hematoxylin and eosin for optical microscopy. Compared with the sham group, jejunal contractions were similar in the IPC + I and the IPC + I/R groups, but reduced in the I + SS and the I/R + SS groups. The jejunal enteric nerves were damaged in the I + SS and the I/R + SS groups, but not in the IPC groups. These results suggested that ischemic preconditioning attenuated intestinal dysfunction caused by I and I/R.

Effects of pentoxifylline on inflammation and lung dysfunction in ventilated septic animals.

Acute respiratory distress syndrome secondary to sepsis is associated with high morbidity and mortality. The purpose of this study was to characterize the effects of ventilatory strategy and the modulating activity of pentoxifylline in a sepsis-induced lung dysfunction model. Male Wistar rats were randomly divided into six groups, undergoing two different ventilatory strategies. Rats received live Escherichia coli or saline intraperitoneally. After 6 hours, the septic animals were treated with either pentoxifylline (25 mg/kg for 20 minutes) or normal saline infusion and ventilated with low tidal volume (6 mL/kg; septic animals with E. coli intraperitoneal [IP] infusion, PTX-treated and ventilated with low tidal volume and septic animals with E. coli IP infusion and ventilated with low tidal volume, respectively) or high tidal volume (12 mL/kg; septic animals with E. coli IP infusion, PTX-treated and ventilated with high tidal volume and septic animals with E. coli IP infusion and ventilated with high tidal volume, respectively) for 3 hours. The control animals received normal saline infusion and, after 6 hours, were ventilated with low or high tidal volume (control animals with saline infusion and ventilated with low tidal volume and control animals with saline infusion and ventilated with high tidal volume, respectively). Lung dysfunctions were assessed by wet-to-dry lung ratios, total cell count, total protein, malondialdehyde, and tumor necrosis factor-alpha concentrations in bronchoalveolar lavage (BAL). Septic animals with E. coli IP infusion and ventilated with high tidal volume presented increased wet-to-dry lung ratios, total cell count, total protein, and malondialdehyde in BAL compared with the septic animals ventilated with low tidal volume. Septic animals treated with pentoxifylline presented higher arterial oxygenation and lower cellular influx, protein leakage, malondialdehyde concentration, and tumor necrosis factor-alpha levels in BAL compared with septic animals undergoing the same ventilatory support strategies (septic animals with E. coli IP infusion and ventilated with low tidal volume and septic animals with E. coli IP infusion and ventilated with high tidal volume). Ventilatory strategy modulated the inflammatory response and pulmonary alterations in a sepsis-induced acute lung injury model, and these effects are improved by pentoxifylline.

Short courses of mechanical ventilation with high-O2 levels in elderly rat lungs

PURPOSE To evaluate the effects of mechanical ventilation (MV) of high-oxygen concentration in pulmonary dysfunction in adult and elderly rats. METHODS Twenty-eight adult (A) and elderly (E), male rats were ventilated for 1 hour (G-AV1 and G-EV1) or for 3 hours (G-AV3 and G-EV3). A and E groups received a tidal volume of 7 mL/kg, a positive end-expiratory pressure of 5 cm H2O, respiratory rate of 70 cycles per minute, and an inspiratory fraction of oxygen of 1. We evaluated total protein content and malondialdehyde in bronchoalveolar lavages (BAL) and performed lung histomorphometrical analyses. RESULTS In G-EV1 animals, total protein in BAL was higher (33.0±1.9 µg/mL) compared with G-AV1 (23.0±2.0 µg/mL). Upon 180 minutes of MV, malondialdehyde levels increased in elderly (G-EV3) compared with adult (G-AV3) groups. Malondialdehyde and total proteins in BAL after 3 hours of MV were higher in elderly group than in adults. In G-EV3 group we observed alveolar septa dilatation and significative increase in neutrofiles number in relation to adult group at 60 and 180 minutes on MV. CONCLUSION A higher fraction of inspired oxygen in short courses of mechanical ventilation ameliorates the parameters studied in elderly lungs.

TNF-α and IL-6 immunohistochemistry in rat renal tissue experimentaly infected with Leptospira interrogans serovar Canicola

Leptospirosis is a public health problem worldwide and its etiology remains unclear. Its pathogenesis involves a complex interaction between host and infecting microorganism. The inflammatory reaction that controls the infection process also underscores many pathophysiological events occurring in leptospirosis. We investigated the presence of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in renal tissues by immunohistochemical and histopathological examination in animals experimentally inoculated with Leptospira serovar Canicola. All the tests were carried out 2, 7, 14, 21 or 28 days after inoculation. Although TNF-α and IL-6 had been detected in tissues throughout the observation period, these cytokines appeared more intensely during the initial phase of infection. Therefore, both TNF-α and IL-6 were associated with the immunopathogenesis of leptospirosis. This profile suggests a high immunocellular response throughout the early infection stages followed by subsequent humoral response.