Protective Effect Of Pentoxifylline Research Articles

The proinflammatory cytokine-mediated protective effects of pentoxifylline, iloprost, and cilostazol on a mitigating lung injury induced by lower limb ischemia and reperfusion in rats

Amac: Bu calismada, pentoksifilin, iloprost ve silostazolun alt ekstremite iskemisi-reperfuzyonu ile tetiklenen akut akciger hasarini azaltip azaltmadigi ve bu koruyucu etkilere sitokinlerin dahil olup olmadigi arastirildi. Ca­lis­ma­ pla­ni:­ Kirk sican rastgele bes gruba ayrildi: kontrol (grup 1), iskemi-reperfuzyon (grup 2), pentoksifilin (grup 3), iloprost (grup 4), iloprost ve silostazol (grup 5). Tum ilaclar iskemi oncesi uygulandi. Tumor nekroz faktor-alfa (TNF-a), interlokin-6 (IL-6) ve total sialik asit (TSA) incelemeleri icin numuneler alindi. Akciger hasari bulgulari incelendi. Bul gu lar: Interlokin-6 ve TNF duzeylerinde 90. dakikada artis oldugu ve hatta 240. dakikadan sonra da yuksek seyrettigi saptandi. Grup 3 ve 4’de, IL-6 ve TNF duzeyleri, grup 2 ile karsilastirildiginda 90, 180. ve 240. dakikalarda anlamli olarak dusuktu. Total sialik asit duzeyleri 180. dakikada grup 2, 3, 4 ve 5’te bazal ve 90. dakikadaki degerlerden anlamli olarak farkli idi. Bu zaman noktasinda TSA duzeyleri grup 2 ve 3’te grup 4 ve 5 ile karsilastirildiginda anlamli derecede yuksekti. So­nuc:­Alt ekstremite I/R ile tetiklenmis bu akut akciger hasari modelinde, pentoksifilin, iloprost ve silostazol ile on tedavinin uygulanmasi, proinflamatuvar aktiviteyi ve parankimal akciger hasarini anlamli duzeyde azaltmistir. Anah tar soz cuk ler: Silostazol; iloprost; iskemi-reperfuzyon hasari; akciger hasari; pentoksifilin. Background:­ This study aims to elucidate whether pentoxifylline, iloprost and cilostazol mitigates acute lung injury induced by lower limb ischemia-reperfusion (I/R) and their protective effects cover cytokines. Methods: Forty rats were randomized into five groups: control (group 1), ischemia-reperfusion (group 2), pentoxifylline (group 3), iloprost (group 4), iloprost and cilostazol (group 5). All drugs were administered before ischemia. Samples were obtained for tumor necrosis factoralpha (TNF-a), interleukin 6 (IL-6), and total sialic acid (TSA) assays. Findings of lung injury were examined. Results:­ Interleukin-6 and TNF levels were increased at 90 minutes and sustained elevated even after 240 minutes. In groups 3 and 4, IL-6 and TNF levels were significantly lower at 90, 180 and 240 minutes compared to group 2. At 180 minutes, TSA levels in groups 2, 3, 4 and 5 were significantly different from baseline and 90 minute levels. At this time point, TSA levels of group 2 and 3 were significantly higher compared to group 4 and 5. Conclusion:­ In this acute lung injury model induced by I/R of the lower limbs, pretreatment with pentoxifylline, iloprost and cilostazol significantly attenuated proinflammatory activities and parenchymal lung damage.

Histological study on the possible protective effect of pentoxifylline on pancreatic acini of l-arginine-induced acute pancreatitis in adult male albino rats

ObjectiveThe aim of this study was to determine the histological changes of l-arginine-induced acute pancreatitis and the possible protective effect of pentoxifylline on pancreatic acini in adult male albino rats.BackgroundAcute pancreatitis is a reversible inflammation that is either localized to the pancreas or may spread to adjoining tissues.Materials and methodsForty adult male albino rats weighing 180-200 g each were used in this study. The rats were divided into four equal groups (10 rats each). Group I was the control group. In group II (l-arginine-treated), rats were administered two intraperitoneal injections of l-arginine at a dose of 200 mg/100 g/body weight with 1-h interval. They were randomly subdivided into two equal subgroups: in IIA, rats were killed after 24 h of the last l-arginine injection and in IIB, rats were killed after 1 week of the last l-arginine injection. In group III (l-arginine and pentoxifylline-treated), rats were administered l-arginine and pentoxifylline. l-arginine was given similar to group II and pentoxifylline was given as a single intraperitoneal injection at a dose of 12 mg/kg body weight/day. They were randomly subdivided into two equal subgroups: in IIIA, rats were given a single dose of pentoxifylline then were killed after 24 h and in subgroup IIIB, rats were given pentoxifylline daily for 1 week then were killed. In group IV (pentoxifylline-treated), rats were administered pentoxifylline as a single intraperitoneal injection of 12 mg/kg body weight/day for 1 week then rats were killed.Resultsl-arginine-treated rats for 24 h showed pancreatic edema, degenerative changes of pancreatic acini, and inflammatory cell infiltration. These changes were marked after 1 week; however, pentoxifylline supplementation in group III showed amelioration of the histological picture, which was marked after daily pentoxifylline treatment for a week.ConclusionIt is concluded that pentoxifylline was found to improve the histological changes of pancreatic acini caused by l-arginine.

Protective effects of pentoxifylline on lipopolysaccharide-induced white matter injury in a rat model of periventricular leukomalasia

Objective: To investigate the potential neuroprotective effect of maternal pentoxifylline (PNTX) treatment in endotoxin-induced periventricular leukomalasia (PVL) in the developing rat brain.Method: Intraperitoneal injection of lipopolysaccharide was administered on two of three Wistar pregnant rats to establish PVL. To obtain PNTX-treated group, one of the two dams were injected with PNTX. The control group was treated with saline. Rat pups were grouped as control, maternal LPS-treated group and PNTX + LPS-treated group. At 7th postnatal days, apoptosis and hypomyelination were evaluated. Apoptosis was evaluated by caspase-3 and terminal deoxynucleotidyl transferase [TdT] dUTP nick endlabelling reaction (TUNEL) immunostaining. To assess hypomyelination, myelin basic protein (MBP) staining, as a marker of myelination, was evaluated.Results: MBP staining was significantly less and weaker in the brains of the LPS-treated group as compared with the PNTX-treated group. PNTX treatment significantly reduced the number of apoptotic cells in the periventricular WM shown on Tunel and caspase-3.Conclusions: Presented study is first indicated that PNTX may provide protection against an LPS-induced inflammatory response and WMI in the developing rat brain. Our results also suggest that PNTX treatment in pregnant women with maternal or placental infection may minimize the risk of PVL and cerebral palsy.

Protective effects of pentoxifylline in pulmonary inflammation are adenosine receptor A 2A dependent

Pentoxifylline (PTX) has been shown to exert anti-inflammatory effects in experimental acute lung injury. However, results in humans were controversial. Recent in vitro studies suggested that the adenosine receptor A2A may be required for PTX to be effective. Therefore, we studied the association between A2A and PTX in a murine model of LPS-induced pulmonary inflammation. PTX treatment (10 mg/kg) reduced cellular influx (by 40%), microvascular permeability (30%), and the release of chemotactic cytokines into the alveolar space (TNF-α 60%, IL-6 60%, and CXCL2/3 53%, respectively). These protective effects were abolished completely in A2A(-/-) mice and in wild-type mice that had been treated with the selective A2A antagonist (1 mg/kg), but effects were not different in mice with altered adenosine levels. In vitro transmigration assays revealed a pivotal role of the endothelium in PTX-mediated PMN migration, with a reduction of 50% (2 mM PTX). This effect was also A2A dependent. Further, oxidative burst of human PMNs was A2A-dependently reduced by 53% after PTX treatment. In summary, PTX exhibits its anti-inflammatory effects in LPS-induced lung injury through an A2A-dependent pathway. These results will help to better understand previous conflicting data on PTX in inflammation and will direct further studies to consider the predominant role of A2A.

Protective effect of pentoxifylline on amikacin-induced ototoxicity in rats

PurposeThis experimental study was performed to investigate the possible protective effect of pentoxifylline (PTX) on amikacin-induced ototoxicity in rats. Materials and methodsIn this study, 21 healthy female rats were randomly assigned to 1 of 3 groups: the amikacin group (n = 8), the amikacin + PTX group (n = 8), and the control group (n = 5). The amikacin group received amikacin (200 mg·kg−1·day−1) intramuscularly once daily for 14 days. The amikacin + PTX group received intramuscular injections of amikacin (200 mg·kg−1·day−1) once daily for 14 days and PTX (25 mg·kg−1·day−1) once daily via gastric gavage for 14 days. The control group received saline solution (1 mL·day−1 intraperitoneal injections) once daily for 14 days. The hearing levels of the rats were evaluated using distortion product otoacoustic emissions before and after treatment. ResultsThe distortion product otoacoustic emissions' amplitude levels (decibel, sound pressure levels) measured before and after treatment at frequencies of 4000, 6000, and 8000 Hz revealed that values of the amikacin group dropped significantly at the end of treatment (P < .01). In contrast, the amikacin + PTX and the control groups showed no significant difference at the end of the treatment compared with the initial measurements (P > .05). ConclusionThe results showed that PTX has protective effects on hearing functions in amikacin-induced ototoxicity in rats.

Protective Effects of Pentoxifylline and Nimodipine on Acoustic Trauma in Guinea Pig Cochlea

To examine the protective effects of the vasodilator and hemorheologically active drug pentoxifylline and the calcium channel blocker nimodipine on the cochlea after acoustic overexposure in guinea pigs. Eighteen guinea pigs were used. The animals were divided into 5 groups: 1) control, 2) acoustic trauma, 3) nimodipine plus acoustic trauma, 4) pentoxifylline plus acoustic trauma, and 5) pentoxifylline plus nimodipine plus acoustic trauma. Nimodipine was given to the guinea pigs 3 mg/kg intraperitoneally in a single dose; pentoxifylline was given 150 mg/kg in a single dose intraperitoneally. A gunnery range was used to create acoustic trauma. The auditory brainstem response of each guinea pig was determined first; then, the animals were killed, and their cochleas were examined under an electron microscope. In the acoustic trauma group, negative auditory brainstem response potentials were seen as was well-adjusted cellular damage to the organ of Corti. In the pentoxifylline group, near-normal auditory brainstem response recordings and organ of Corti histologic findings were found. Organ of Corti damage was seen in the pentoxifylline plus nimodipine plus acoustic trauma group. We determined that pentoxifylline was highly protective against noise, but nimodipine was not. Also, pentoxifylline and nimodipine, when used together, increased damage to the organ of Corti.

Protective effects of pentoxifylline on cigarette smoking-induced renal tissue damage in rats

In this study, we investigated the protective effect of pentoxifilline (PTX) on smoking-induced damage in rat kidney tissues. Twenty-seven male Wistar rats were used in the study. Animals were divided into three equal groups as follows: Group 1: control group with only normal saline (NS; 0.9% NaCl) injection for 8 weeks; Group 2: cigarette smoking and NS injection for 8 weeks; and Group 3: cigarette smoking and PTX injection for 8 weeks. The rats were sacrificed after 8 weeks and their kidneys were excised for histopathological analysis. Serial paraffin sections (5 µm) of the kidneys were cut and stained with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS). The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) method was used to assess apoptosis. Glomerular diameters, glomerular cell number and proximal tubule cell numbers were compared between the groups. Our results showed that PTX treatment prevented negative effects of smoking in rat kidneys. There was a statistically significant difference in all assessed parameters between Group 2 and other groups (p < 0.05). In conclusion, our study shows that PTX treatment is effective in preventing the negative effects of cigarette smoking on kidneys by inhibiting cell damage with its antioxidant properties.

Protective effects of pentoxifylline on the brain following remote burn injury

Introduction Brains are often subject to injurious effect following remote burn injury and increased productions of inflammatory cytokines are involved. It is also known that pentoxifylline (PTX) exerts multiple beneficial effects on the inflammatory cascade. Therefore, we investigated whether a single dose of PTX given immediately following severe remote burn would protect the brain from the injurious effects. Methods Rats were divided randomly into the sham burn group, burn placebo-treated group and burn PTX-treated group. Single dose of PTX was injected 15 min following initial burn injury. We measured the levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 in the brain tissue at 0.5, 1, 2, 4, 8 and 16 h after burn. Other measures included the level of nuclear factor-kappaB (NF-κB) activation, glial activation and apoptosis of cortical cells. Results PTX substantially suppressed the burn-induced surge in the levels of TNF-α, IL-1β, and IL-6 in the rat-brain tissues. PTX reduced the level of burn-induced apoptosis. PTX also significantly reduced the activation of nuclear transcription factor NF-κB and reduced the activation of glial cells in the brain tissue. Conclusion An early, single dose of PTX dramatically reduced brain inflammation and apoptosis for up to 16 h post-injury.

Protection by pentoxifylline of malathion-induced toxic stress and mitochondrial damage in rat brain

The objective of this study was to investigate the possible protective effects of pentoxifylline as a phosphodiesterase-5 inhibitor on malathion-induced oxidative damage to rat brain mitochondria. Rats received malathion (200 mg/kg/day) and pentoxifylline (PTX, 50 mg/kg/day) in combination or alone. Alpha-tocopherol (AT, 15 mg/kg/day) was used as a positive standard. After 1 week of treatment, blood, whole brain tissue, and brain mitochondria were isolated. The activity of enzymatic scavengers such as glutathione peroxidase (GPx), catalase (CAT), copper-zinc superoxide dismutase (Cu/ZnSOD), and manganese superoxide dismutase (MnSOD) were measured. The extents of cellular lipid peroxidation (LPO), nitrotyrosine (NOx), and the ratio of reduced versus oxidized glutathione (GSH/GSSG) were determined. The protein expression of MnSOD was determined in brain mitochondria. Malathion stimulated activities of CAT, Cu/ZnSOD, GPx, and increased LPO and NOx, and decreased GSH/GSSG in whole brain homogenate. The changes in CAT, LPO, GPx, and GSH/GSSG were restored by PTX and AT. In plasma samples, malathion increased CAT, Cu/ZnSOD, and GPx activities, increased LPO, and decreased GSH/GSSG, while PTX and AT attenuated malathion-induced changes in GPx, Cu/ZnSOD, LPO, and GSH/GSSG. In brain mitochondria, malathion enhanced LPO, NOx, CAT, GPx, and MnSOD and decreased GSH/GSSG as compared to controls, whereas PTX and AT restored malathion-induced changes in GSH/GSSG, NOx, GPx, and CAT. Malathion noticeably enhanced expression of MnSOD protein as compared to controls. Malathion decreased viability of mitochondria that was recovered by AT. It is concluded that oxidative damage is at least in part the mechanism of toxicity of malathion in the mitochondria that can be recovered by PTX comparable to AT.

Interaction of phosphodiesterase 5 inhibitor with malathion on rat brain mitochondrial-bound hexokinase activity

The main objective of this study was to investigate the possible protective effect of pentoxifylline as a phosphodiesterase 5 inhibitor used as a cardiovascular medication on malathion-induced changes on rat mitochondrial-bound hexokinase activity. Animals in four various groups received moderate toxic dose of malathion (200 mg/kg/day), effective dose of pentoxifylline (50 mg/kg/day) alone and in combination, and the control group that received only vehicle. All administrations were done intraperitoneally for one week. At the end of the experiment, the brain was removed and the mitochondria were isolated. Hexokinase (HK) activity, cellular lipid peroxidation (LPO) and total antioxidant capacity (TAC) were analyzed in brain mitochondria. Malathion noticeably decreased TAC and increased HK activity and LPO in the mitochondria whereas pentoxifylline significantly restored malathion-induced changes in LPO, HK, and TAC. The results of the present study indicate that phosphodiesterase 5 inhibition remarkably protects brain mitochondria from malathion-induced changes on HK activity and oxidative stress.

Protective effects of pentoxifylline on gastric mucosal injury in rats with endotoxemia

Objective To investigate the protective effects of pentoxifylline on gastric mucosal injury in rats with endotoxemia. Methods 30 Wistar rats were randomly divided into 3 groups : sham operated control group (C group) ,LPS group and PTX group. The serum tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) levels in each group were measured. The immunohistochemistry was used to assess the expression of the ICAM-1 in the gastric mucosal tissues. Results The levels of TNF-α and IL-1β in serum in LPS group were higher than those in C group (P <0.01). The level of ICAM-1 in the gastric mucosal tissues in LPS group was higher than those in sham operated control group(P < 0.01). After FIX treatment, the levels of TNF-α and IL-1β in serum in PTX group were lower than those in LPS group(P < 0.01) and the level of ICAM-1 in the hepatic tissues in PTX group was also lower than those in LPS group(P <0.01). Conclusions TNF-α,IL-1β and ICAM-1 take part in the progress of gastric mucosal inju-ry in rats with endotoxemia. PTX can eliminate the gastric mueesa injury and protect the gastric mucosal tissues by downregulating the levels of TNF-α, IL-1β and ICAM-1. Key words: Pentoxifylline; Endotoxemia; Gastric mucosa; injury; Intercellular adhesion molecule-1

Effect of pentoxifylline on diaphragmatic contractility in septic rats.

We investigated the effects of pentoxifylline (PTX) on endotoxin-induced diaphragmatic dysfunction in vitro. Seventy-two rats were divided into 3 groups: a group in which endotoxin (20 mg/kg) was injected intraperitoneally (endotoxin-group), a group in which PTX (100 mg/kg) was injected intraperitoneally 30 min before injection of endotoxin (endotoxin-PTX group), and a group in which only saline was given (sham group). Left hemidiaphragms were removed 4 h after injection of endotoxin. We evaluated the diaphragmatic contractility by twitch characteristics and force-frequency curves in vitro. We measured serum TNF-alpha concentrations, diaphragm malondialdehyde (MDA) levels (an index of oxygen-derived free radical-mediated lipid peroxidation), and diaphragm cAMP concentrations. Diaphragmatic force generation capacity was signifi cantly reduced after injection of endotoxin. Serum TNF-alpha concentrations and diaphragmatic MDA levels were significantly elevated after injection of endotoxin. PTX administration significantly improved diaphragmatic contractility and prevented the elevation in TNF-alpha concentrations and MDA levels after injection of endotoxin. There were no significant changes in the diaphragm cAMP concentrations among the 3 groups. These results demonstrated that PTX administration prevented endotoxin-induced diaphragmatic dysfunction without changing diaphragm muscle cAMP concentrations. The protective effects of PTX against endotoxininduced diaphragmatic contractile deterioration might be caused by attenuating TNF-alpha-mediated oxygen-derived free radical production.

Protective Effect of Pentoxifylline on Growth Plate in Neonatal Rats Following Long-Term Phototherapy

Protective Effect of Pentoxifylline on Growth Plate in Neonatal Rats Following Long-Term Phototherapy

Protective Effect of Pentoxifylline on Growth Plate in Neonatal Rats Following Long-Term Phototherapy

We demonstrated previously that receiving long-term phototherapy was associated with early impairment of growth plate structure in neonatal rats, and oxidative stress may be the main risk factor for growth plate injury. The purpose of this study was to examine the histomorphometric effects of pentoxifylline treatment on the growth plate. Sixty weanling Sprague-Dawley rats were randomly separated into three equal groups. Group A, the control group, did not receive phototherapy and pentoxifylline. Groups B and C were exposed to phototherapy for 7 d. In addition to phototherapy, group C was also given pentoxifylline during the study period. Compared with zonal lengths on d 7 after initiation of phototherapy, group B had significantly lower values than group A for all zonal lengths (p < 0.001). Zonal lengths of growth plate were increased significantly with pentoxifylline treatment in group C for 7 d compared with group B (p < 0.001). After phototherapy, group B had significantly higher values than groups A and C for plasma malondialdehyde levels (p < 0.001). The pentoxifylline was found here to have some potential to reduce the effects of phototherapy on growth plate in neonatal rats at a relatively low dose.

Influence of maternal nicotine exposure on neonatal rat bone: protective effect of pentoxifylline.

Limited research in young adults and immature animals suggests a detrimental effect of tobacco on bone during growth. The aim of this study was to determine the adverse effects of maternal nicotine exposure during pregnancy and lactation on neonatal rat bone development, and to determine a protective effect of pentoxifylline (PTX). Gravid rats were assigned into four groups, one control (group I) and three experimental (groups II, III, and IV). In group II, pregnant rats received 3 mg/kg/day nicotine alone, subcutaneously, until 21 days postnatal. In group III, pregnant rats received nicotine (3 mg/kg/day) and PTX (60 mg/kg/day). In group IV, pregnant rats received PTX alone (60 mg/kg/day). Whole body mineral density (BMD), content (BMC), area (BA), and histopathologic and morphologic findings of the femur were determined at 21 days of age. The study revealed that nicotine exposure (group II) decreased birth weight, pregnancy weight gain, and length of femur compared with other groups (P < 0.01). Birth weight was higher in groups III (PTX + nicotine) and IV (PTX) than in group II (nicotine). Body weight at 21 days of age was higher (P = 0.009) in the PTX alone group (group IV) compared with the other groups. BMD was higher (P < 0.001) in the PTX-treated groups (group III and IV) compared with other groups. In addition, there were more apoptotic chondrocytes in the hypertrophic zone of rats exposed to nicotine alone (group II) compared with the other groups (P < 0.001). In conclusion, maternal nicotine exposure resulted in decreased birth weight, pregnancy weight gain, and bone lengthening, and increased apoptosis. Pentoxifylline supplementation was found to prevent the adverse effects of maternal nicotine exposure on BMD and birth weight.

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.

Pentoxifylline Improves Reoxygenation-induced Contractile Recovery Through a Nitric Oxide-dependent Mechanism in Rat Papillary Muscles

In this study, the protective effect of pentoxifylline against hypoxia-reoxygenation injury and the possible involvement of nitric oxide (NO)-mediated pathways in this protection were investigated in isolated rat papillary muscles. Papillary muscles were excised and isolated in Krebs-Henseleit solution aerated with 95% O2 and 5% CO2. Hypoxia was simulated by substituting O2 with argon. Three sets of experiments, testing 30, 60, and 90 min of hypoxia, were performed. The effects of different pentoxifylline concentrations on papillary muscle contractile parameters and responsiveness to isoproterenol were assessed. To investigate the role of NO, N(omega)-nitro-L-arginine methyl ester was added before pentoxifylline treatment. Pentoxifylline did not show any inotropic effect on papillary muscles. Hypoxia caused a profound depression of contractile parameters, which was not affected by pentoxifylline treatment. Reoxygenation resulted in significant partial recovery of contractile parameters after 30 and 60 but not 90 min of hypoxia. In experiments with 30 and 60 min of hypoxia, reoxygenation-induced contractile recovery and responsiveness to isoproterenol were improved by pentoxifylline in a concentration-dependent fashion. These functional improvements were completely blocked by N(omega)-nitro-L-arginine methyl ester pretreatment. No improvement was observed in 90-min hypoxia experiment. In conclusion, pentoxifylline improved contractile recovery during reoxygenation and postreoxygenation responsiveness to beta-adrenergic stimulation through the NO-dependent mechanism.

Kupffer cell-dependent TNF-α signaling mediates injury in the arterialized small-for-size liver transplantation in the mouse

Implantation of small liver grafts causes liver injury and defective regeneration leading to graft failure. We investigated whether Kupffer cell-dependent TNF-alpha signaling contributes to this poor outcome. Partial 30% liver transplantation was performed in C57BL/6 wild-type mice (control group), and in three groups with down-regulation of the TNF-alpha pathway: (i) TNF receptor 1 knockout [TNFR-1(-/-)] mice, and mice pretreated with (ii) gadolinium chloride or (iii) pentoxifylline (PTX). Fifty-percent partial liver transplantation, a model associated with full recovery, and transplantation in IL-6 knockout [IL-6(-/-)] mice were performed in some experiments. Graft injury, regeneration, portal flow, liver microcirculation, leukocyte adhesion, and animal survival were assessed. Animal survival rates were 14% in the control group vs. 43% in the gadolinium chloride group, 57% for the TNFR-1(-/-) group, and 86% in the PTX group (P < 0.001). Markers of liver injury were reduced in all treated groups when compared with controls. Each treated group disclosed better portal flow and sinusoid perfusion, decreased leukocyte adherence, particularly in the PTX group. Liver regeneration occurred only in the treated groups. IL-6 and IL-10 levels were dramatically up-regulated (50x) in the PTX group, and at lower levels in other experimental groups. The protective effect of PTX was lost in IL-6(-/-) mice and protection was restored by a single dose of r-IL-6. In conclusion, interruption of TNF-alpha signaling or depletion of Kupffer cells improves survival after 30% liver transplantation, reduces liver injury, and enhances regeneration. The superior effects of PTX are mediated by IL-6.

Effects of the tumour necrosis factor‐α inhibitors pentoxifylline and thalidomide in short‐term experimental oral mucositis in hamsters

Oral mucositis is a frequent side-effect of cancer therapy. A definitive method of prophylaxis or treatment is not yet available. As pentoxifylline (PTX) and thalidomide (TLD) have been shown to inhibit cytokine synthesis, we studied the effects of these cytokine inhibitors in an experimental oral mucositis model. Oral mucositis was induced in Golden hamsters by the administration of 5-fluorouracil (5-FU) followed by mechanical trauma of the cheek pouch. On days 4, 5, 10, 12, 14 and 16, lesions induced by 5-FU were examined macroscopically and microscopically, and the presence and intensity of hyperemia, erythema, edema, inflammatory cell infiltration, hemorrhagic areas, ulcers and abscesses were recorded. Saline (control), PTX (5, 15, 45 mg kg(-1)) or TLD (10, 30, 90 mg kg(-1)) were administered daily and animals were killed on day 10 for macroscopic and histological analysis and assay of myeloperoxidase (MPO) activity. Animals were weighed daily, and total and differential leukocyte counts were performed on peripheral blood. PTX and TLD were found to reduce the macroscopic and histological parameters of oral mucositis and MPO activity. PTX and TLD also reversed peripheral neutrophilia, but only PTX prevented weight loss. The results indicate a protective effect of PTX and TLD, suggesting an important role for tumour necrosis factor-alpha (TNF-alpha) in the pathophysiology of 5-FU induced-oral mucositis in hamsters.

Protective Effect of Pentoxifylline on Volume-Induced Lung Injury in Newborn Piglets

To evaluate the efficacy of pentoxifylline (PTXF) in the attenuation of lung inflammation during volume-induced lung injury (VILI) in newborn piglets, 17 newborn piglets were mechanically ventilated with a large tidal volume (50 ml/kg) for a period of 8 h. They were randomly assigned to a placebo (PL, n = 9) or a treatment group (PTXF, n = 8) that received PTXF (20 mg/kg as a bolus, followed by a continuous infusion of 5 mg/kg/h). Hemodynamics, lung mechanics and arterial blood gases were measured during the 8 h of study. Serum and tracheoalveolar fluid (TAF) platelet-activating factor (PAF) and thromboxane (TXB₂) levels were obtained at baseline and at 8 h, while lung tissue myeloperoxidase (MPO) and wet to dry weight were assessed after the completion of the study. In the PL group, a marked increase in TAF PAF and TXB₂ levels was observed only in TAF, suggesting that the inflammatory process was localized within the lungs. A significant decrease in lung tissue MPO activity (p < 0.005) and lung wet to dry weight ratio (p < 0.04) was observed in the PTXF group. There were no differences in hemodynamics, arterial blood gases or lung mechanics measurements between groups. A significant reduction in pulmonary inflammatory response was observed during VILI in the PTXF pretreated animals. These results suggest that PTXF may be effective in modulating lung inflammation associated with mechanical ventilation in neonates.