Infection of schistosomiasis japonica may eventually lead to liver fibrosis, and no effective antifibrotic therapies are available but liver transplantation. Hedgehog (HH) signaling pathway has been involved in the process and is a promising target for treating liver fibrosis. This study aimed to explore the effects of pentoxifylline (PTX) on liver fibrosis induced by schistosoma japonicum infection by inhibiting the HH signaling pathway. Phorbol12-myristate13-acetate (PMA) was used to induce human acute mononuclear leukemia cells THP-1 to differentiate into macrophages. The THP-1-derived macrophages were stimulated by soluble egg antigen (SEA), and the culture supernatants were collected for detection of activation of macrophages. Cell Counting Kit-8 (CCK-8) was used to detect the cytotoxicity of the culture supernatant and PTX on the LX-2 cells. The LX-2 cells were administered with activated culture supernatant from macrophages and(or) PTX to detect the transforming growth factor-β gene expression. The mRNA expression of shh and gli-1, key parts in HH signaling pathway, was detected. The mRNA expression of shh and gli-1 was increased in LX-2 cells treated with activated macrophages-derived culture supernatant, suggesting HH signaling pathway may play a key role in the activation process of hepatic stellate cells (HSCs). The expression of these genes decreased in LX-2 cells co-cultured with both activated macrophages-derived culture supernatant and PTX, indicating PTX could suppress the activation process of HSCs. In conclusion, these data provide evidence that PTX prevents liver fibrogenesis in vitro by the suppression of HH signaling pathway.
Animals ; Antigens, Helminth ; isolation & purification ; pharmacology ; Cell Culture Techniques ; Cell Differentiation ; drug effects ; Cell Line ; Culture Media, Conditioned ; chemistry ; pharmacology ; Gene Expression Regulation ; Hedgehog Proteins ; agonists ; antagonists & inhibitors ; genetics ; immunology ; Hepatic Stellate Cells ; cytology ; drug effects ; metabolism ; Humans ; Liver Cirrhosis ; metabolism ; parasitology ; prevention & control ; Macrophage Activation ; drug effects ; Macrophages ; cytology ; drug effects ; immunology ; Models, Biological ; Monocytes ; cytology ; drug effects ; metabolism ; Pentoxifylline ; pharmacology ; Phosphodiesterase Inhibitors ; pharmacology ; RNA, Messenger ; genetics ; immunology ; Schistosoma japonicum ; chemistry ; Signal Transduction ; Tetradecanoylphorbol Acetate ; pharmacology ; Zinc Finger Protein GLI1 ; genetics ; immunology ; Zygote ; chemistry

Diabetic nephropathy (DN) is a common and serious clinical complication of diabetes and presently there are no effective ways to prevent its occurrence and progression. Recent studies show that pentoxifylline (PTX) can improve renal hemodynamics, reduce urinary protein excretion, and alleviate or delay renal failure in DN patients. In this study, we focused on the anti-oxidative stress effect of PTX on alleviating renal damages of DN using rat models. DN rats were established with injection of streptozotocin. Blood glucose, urinary protein excretion, serum cystatin C, renal biopsy, superoxide dismutase (SOD) and malondialdehyde (MDA) in serum and renal homogenate and renal nitrotyrosine levels were analyzed before and 12 weeks after the treatment of PTX. Before treatment, all the DN rats had elevated blood glucose, increased urinary protein excretion and elevated serum cystatin C. Morphologically, DN rats exhibited renal tissue damages, including swelling and fusions of foot processes of podocytes under electron microscope. Masson staining revealed blue collagen deposition in glomeruli and renal interstitium. With treatment of PTX, symptoms and renal pathological changes of DN rats were alleviated. Furthermore, the MDA levels were increased and the SOD levels were decreased in the serum and kidneys of DN rats, and these changes were reversed by PTX. The expression of nitrotyrosine was up-regulated in DN rat model and down-regulated by PTX, indicating that PTX was able to inhibit oxidative reactions in DN rats. PTX could alleviate renal damage in DN, which may be attributable to its anti-oxidative stress activity.
Animals ; Biomarkers ; analysis ; Diabetes Mellitus, Experimental ; drug therapy ; pathology ; Diabetic Nephropathies ; drug therapy ; metabolism ; pathology ; Gene Expression Regulation ; drug effects ; Kidney ; metabolism ; pathology ; Malondialdehyde ; blood ; Oxidative Stress ; drug effects ; Pentoxifylline ; administration & dosage ; pharmacology ; Rats ; Streptozocin ; Superoxide Dismutase ; metabolism ; Tyrosine ; analogs & derivatives ; metabolism

PURPOSE: Limited studies have shown antifibrotic effects of pentoxifylline, captopril, simvastatin, and tamoxifen. No comparisons are available of the effects of these drugs on prevention of renal and bladder changes in partial urethral obstruction (PUO). MATERIALS AND METHODS: The rats were divided into six groups (n=7). The sham-operated rats (group I) only underwent laparotomy and did not receive any treatments. The PUO groups (group II-VI) received normal saline (PUO+NS), pentoxifylline (100 mg/kg/d; PUO+PEN), captopril (35 mg/kg/d; PUO+CAP), simvastatin (15 mg/kg/d; PUO+SIM), or tamoxifen (10 mg/kg/d; PUO+TAM) by gavage for 28 days. Then, the volume and/or length of the kidney components (tubules, vessels, and fibrous tissue) and the bladder components (epithelial and muscular layers, fibrous tissue, fibroblast and fibrocyte number) were quantitatively evaluated on the microscopic sections by use of stereological techniques. RESULTS: The volume of renal and bladder fibrosis was significantly ameliorated in the PUO+PEN group, followed by the PUO+CAP, PUO+SIM, and PUO+TAM groups. Also, the volume and length of the renal tubules and vessels and bladder layers were more significantly protected in the PUO+PEN group, followed by the PUO+CAP, PUO+SIM, and PUO+TAM groups. CONCLUSIONS: Treatment of PUO with PEN was more effective in the prevention of renal and bladder fibrosis and in the preservation of renal and bladder structures.
Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Animals ; Captopril/*pharmacology ; Disease Models, Animal ; Estrogen Antagonists/pharmacology ; Free Radical Scavengers/pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Kidney/*drug effects/pathology ; Male ; Pentoxifylline/*pharmacology ; Rats ; Simvastatin/*pharmacology ; Tamoxifen/*pharmacology ; Urethral Obstruction/*drug therapy ; Urinary Bladder Neck Obstruction/*drug therapy

No abstract available.
Animals ; Anoxia/*drug therapy ; Diabetes Mellitus, Experimental/*complications ; Diabetic Nephropathies/*drug therapy ; Kidney Tubules/*drug effects ; Male ; Pentoxifylline/*pharmacology ; Phosphodiesterase Inhibitors/*pharmacology

BACKGROUND/AIMS: Renal hypoxia is involved in the pathogenesis of diabetic nephropathy. Pentoxifyllin (PTX), a nonselective phosphodiesterase inhibitor, is used to attenuate peripheral vascular diseases. To determine whether PTX can improve renal hypoxia, we investigated its effect in the streptozocin (STZ)-induced diabetic kidney. METHODS: PTX (40 mg/kg, PO) was administered to STZ-induced diabetic rats for 8 weeks. To determine tissue hypoxia, we examined hypoxic inducible factor-1alpha (HIF-1alpha), heme oxygenase-1 (HO-1), vascular endothelial growth factor (VEGF), and glucose transporter-1 (GLUT-1) levels. We also tested the effect of PTX on HIF-1alpha in renal tubule cells. RESULTS: PTX reduced the increased protein creatinine ratio in diabetic rats at 8 weeks. HIF-1alpha, VEGF, and GLUT-1 mRNA expression increased significantly, and the expression of HO-1 also tended to increase in diabetic rats. PTX significantly decreased mRNA expression of HIF-1alpha and VEGF at 4 and 8 weeks, and decreased HO-1 and GLUT-1 at 4 weeks. The expression of HIF-1alpha protein was significantly increased at 4 and 8 weeks in tubules in the diabetic rat kidney. PTX tended to decrease HIF-1alpha protein expression at 8 weeks. To examine whether PTX had a direct effect on renal tubules, normal rat kidney cells were stimulated with CoCl2 (100 microM), which enhanced HIF-1alpha mRNA and protein levels under low glucose conditions (5.5 mM). Their expressions were similar even after high glucose (30 mM) treatment. PTX had no effect on HIF-1alpha expression. CONCLUSIONS: PTX attenuates tubular hypoxia in the diabetic kidney.
Animals ; Anoxia/*drug therapy/enzymology/etiology/genetics ; Cell Line ; Cobalt/pharmacology ; Diabetes Mellitus, Experimental/*complications ; Diabetic Nephropathies/*drug therapy/enzymology/etiology/genetics ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Glucose/metabolism ; Glucose Transporter Type 1/genetics ; Heme Oxygenase (Decyclizing)/genetics/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Kidney Tubules/*drug effects/enzymology ; Male ; Pentoxifylline/*pharmacology ; Phosphodiesterase Inhibitors/*pharmacology ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Streptozocin ; Time Factors ; Vascular Endothelial Growth Factor A/genetics

No abstract available.
Animals ; Anoxia/*drug therapy ; Diabetes Mellitus, Experimental/*complications ; Diabetic Nephropathies/*drug therapy ; Kidney Tubules/*drug effects ; Male ; Pentoxifylline/*pharmacology ; Phosphodiesterase Inhibitors/*pharmacology

BACKGROUNDCigarette smoke-induced emphysema is associated with overexpression of the chemokine receptor CXCR3 and its ligands. Previously, we have demonstrated that pentoxifylline (PTX) alleviated cigarette smoke-induced emphysema. The aim of this study was to determine if the overexpression of CXCR3 and its ligand interferon-inducible protein-10 (IP-10) that was elicited by smoke exposure were attenuated by PTX.

METHODS(1) The study in vitro: a given number of RAW264.7 macrophages with decreasing concentrations of PTX in the culture medium were challenged with cigarette smoke extract (CSE); (2) The study in vivo: male BALB/c mice were randomized into four groups, i.e., sham-smoke, smoke only, smoke with 2 mg/kg PTX, and smoke with 10 mg/kg PTX. The smoke exposure time was 90 minutes once a day, 6 days a week for 16 weeks. PTX was given intraperitoneally before each episode of smoke exposure. Interferon (IFN)-γ and IP-10 in broncho-alveolar lavage fluid (BALF) and in culture medium were measured by enzyme-linked immunosorbent assay (ELISA). IP-10 mRNA in lung tissue was assessed by RT-PCR. CXCR3 positive cells in lung sections were visualized by immunochemistry staining.

RESULTSUp-regulation of IFN-γ and IP-10 in the culture medium of macrophages elicited by CSE was inhibited by PTX in a dose-dependent manner. Chronic cigarette smoke exposure led to overexpression of IFN-γ and IP-10 in BALF, upregulation of IP-10 mRNA and increased infiltration of CXCR3(+) cells into lung parenchyma. Administration of PTX decreased the level of IFN-γ from (6.26 ± 1.38) ng/ml to (4.43 ± 0.66) ng/ml by low dose PTX or to (1.74 ± 0.28) ng/ml by high dose PTX. IP-10 was reduced from (10.35 ± 1.49) ng/ml to (8.19 ± 0.79) ng/ml by low dose PTX or to (7.51 ± 0.60) ng/ml by high dose PTX. The expression of IP-10 mRNA was also down-regulated (P < 0.05). But only with a high dose of PTX was the ratio of CXCR3(+) cells decreased; 15.2 ± 7.3 vs. 10.4 ± 1.8 (P < 0.05).

CONCLUSIONPTX attenuates cigarette smoke-induced overexpression of chemokine receptor CXCR3 and its ligand IP-10, which is relevant to its inhibitory effect on pulmonary emphysema.

Animals ; Cell Line ; Chemokine CXCL10 ; genetics ; metabolism ; Gene Expression ; drug effects ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred BALB C ; Pentoxifylline ; pharmacology ; therapeutic use ; Pulmonary Emphysema ; drug therapy ; genetics ; metabolism ; Random Allocation ; Receptors, CXCR3 ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Smoking ; adverse effects

OBJECTIVETo investigate the influence of high-voltage electrical burn (HEB) on the aggregation and adhesion of platelet and leukocyte in rats and the interventional effect of pentoxifylline (PTX).

METHODSOne hundred and eighty SD rats were divided into control, electrical burn (EB), and pentoxifylline treatment (PT) groups according to the random number table, with 60 rats in each group. (1) Ten rats were taken from each group at 15 minutes before injury for the observation of the microcirculatory perfusion of chest skin with Laser Doppler Perfusion Imager (LDPI), and the number of leukocyte adherent to mesenteric venule with Bradford Variable Projection Microscope (BVPM). Serum was collected from heart blood to determine the contents of platelet activating factor (PAF), thromboxane B2 (TXB2), prostacyclin (PGI2), P-selectin, E-selectin and L-selectin by double-antibody sandwich enzyme-linked immunosorbent assay. The ratio of TXB2 to PGI2 was calculated therefrom. (2) Model of HEB was reproduced in the remaining 50 rats of EB group and that of PT group with voltage regulator and experimental transformer (the electrical current applied to the left forelimb and exited from the right hind limb). The remaining 50 rats of control group were sham injured with the same devices without electric current. Within 2 minutes post injury (PIM), rats in control group and EB group were intraperitoneally injected with 2 mL isotonic saline, while rats in PT group were intraperitoneally injected with 2 mL pentoxifylline (50 mg/mL). At PIM 5 and 1, 2, 4, 8 hour(s) post injury (PIH), 10 rats of every group were randomly chosen at each time point for the observation of the microcirculatory perfusion of chest skin and the number of leukocytes adherent to mesenteric venule through the same method as used above, and the levels of the related factors of aggregation and adhesion of platelets and leukocytes were determined, and then the relative ratio was calculated. Data were processed with the analysis of variance of factorial design and LSD test.

RESULTSThe contents of PAF, TXB2, PGI2, P-selectin, E-selectin, L-selectin, and the ratio of TXB2 to PGI2, as well as the number of adhered leukocyte in EB group were higher, while the microcirculatory perfusion value was lower than those of control group, with F values from 854.20 to 8156.52, P values all below 0.01. The microcirculatory perfusion value and PGI2 content of PT group were higher, while the contents or number of other indexes were lower than those of EB group, with F values from 33.18 to 1033.99, P values all below 0.01. Only the data within EB group and PT group were comparable. The contents of PAF, TXB2, PGI2, P-selectin, E-selectin, L-selectin, and the ratio of TXB2 to PGI2, as well as the number of adhered leukocyte in EB group and PT group at each time point were significantly higher than those at 15 minutes before injury, while the microcirculation perfusion value was significantly lower than that at 15 minutes before injury (P values all below 0.001), with the exception of the ratio of TXB2 to PGI2 in PT group and E-selectin in EB group and PT group at PIM 5. The contents of PAF, TXB2, and E-selectin and the ratio of TXB2 to PGI2 in EB group peaked at PIH 4, and they were respectively (9.3 ± 0.9) ng/mL, (14.31 ± 0.65) nmol/mL, (271.2 ± 18.4) ng/mL and 4.62 ± 0.26. The contents of PGI2 and P-selectin, and the number of adhered leukocyte in EB group peaked at PIH 8, and they were respectively (3.98 ± 0.24) nmol/mL, (514 ± 24) ng/mL, and (25.50 ± 4.14) per 100 µm venule. The content of L-selectin peaked at PIH 2 [(876 ± 54) ng/mL]. The microcirculatory perfusion value was lowest at PIM 5 [(1.17 ± 0.10) V].

CONCLUSIONSHEB can increase the contents of PAF, TXB2, PGI2, P-selectin, E-selectin, L-selectin, the ratio of TXB2 to PGI2, and the number of adhered leukocyte, as well as decrease the skin microcirculatory perfusion value. PTX can inhibit the aggregation and adhesion of platelets and leukocytes through increasing the content of PGI2 and decreasing contents of other factors mentioned above, thus alleviating the microcirculatory dysfunction after HEB.

Animals ; Blood Platelets ; drug effects ; Burns, Electric ; blood ; physiopathology ; Leukocytes ; drug effects ; physiology ; Male ; Pentoxifylline ; pharmacology ; Platelet Aggregation ; drug effects ; Rats ; Rats, Sprague-Dawley

BACKGROUNDPrevious discovery that long-term administration of pentoxifylline (PTX) to mice chronically exposed to smoke led to the development of pulmonary fibrosis rather than emphysema initiated our curiosity on whether the Wnt/β-catenin pathway, a set of signaling proteins essential to organ development and lung morphogenesis in particular were activated in the pathogenesis of pulmonary fibrosis.

METHODSMale BALB/c mice were randomized into four study groups: Group Sm, smoke exposure and taken regular forage; Group PTX, no smoke but taken PTX-rich forage; Group Sm + PTX, smoke exposure and taken PTX-rich forage; Group control: shamed smoke exposure and taken regular forage. Animals were sacrificed at day 120. Morphometry of the lung sections and the expressions of TGF-β(1), hydroxyproline, β-catenin, cyclin D1, T cell factor 1 (Tcf-1) and lymphoid enhancer factor 1 (Lef-1) mRNA, etc, in the lung homogenate or in situ were qualitatively or quantitatively analyzed.

RESULTSAs expected, smoke exposure along with PTX administration for 120 days, lungs of the mice progressed to be a fibrosis-like phenotype, with elevated fibrosis score (3.9 ± 1.1 vs. 1.7 ± 0.6 in Group Sm, P < 0.05). TGF-β(1) (pg/g) (1452.4 ± 465.7 vs. 818.9 ± 202.8 in Group Sm, P < 0.05) and hydroxyproline (mg/g) (5.6 ± 0.6, vs. 2.4 ± 0.1 in Group Sm, P < 0.05) were also consistently increased. The upregulation of β-catenin measured either by counting the cell with positive staining in microscopic field (17.4 ± 7.9 vs. 9.9 ± 2.9 in Group Sm, P < 0.05) or by estimation of the proportion of blue-stained area by Masson's trichrome (11.8 ± 5.6 vs. 4.7 ± 2.4 in Group Sm) in Group SM + PTX was much more noticeable as than those in Group Sm. The expression of β-catenin measured by positive cell counts was correlated to TGF-β(1) concentration in lung tissue (r = 0.758, P < 0.001). PTX per se caused neither fibrosis nor emphysema though expression of β-catenin and downstream gene cyclin D(1) may also be altered by this medication.

CONCLUSIONSPTX mediated transformation of pulmonary emphysema into pulmonary fibrosis under chronic cigarette smoke exposure is associated with upregulation of β-catenin and elevation of TGF-β(1), implying that activation of Wnt/β-catenin signaling may be involved in the pathogenesis of pulmonary fibrosis.

Animals ; Blotting, Western ; Female ; Immunohistochemistry ; Mice ; Mice, Inbred BALB C ; Pentoxifylline ; pharmacology ; Pulmonary Emphysema ; chemically induced ; metabolism ; Pulmonary Fibrosis ; chemically induced ; metabolism ; Random Allocation ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; drug effects ; genetics ; Tobacco Smoke Pollution ; adverse effects ; Transforming Growth Factor beta1 ; metabolism ; Wnt Proteins ; metabolism ; beta Catenin ; metabolism

OBJECTIVETo investigate the effect of pentoxifylline on one-lung ventilation injury in rabbits.

METHODSTwenty rabbit models of one-lung ventilation by intrabronchial intubation after tracheotomy were randomly allocated in control group (with one-lung ventilation) and experiment group (with one-lung ventilation and intravenous pentoxifylline administration). One-lung ventilation was maintained for 3 h in both groups using the volume-control mode (tidal volume of 8 ml/kg at the frequency of 30 per min). Arterial blood samples were taken after anesthesia and at 3 h of one-lung ventilation for arterial blood gas analysis to obtain the oxygenation index. At the end of the experiment, the pulmonary wet/dry ratio (W/D), tumor necrosis factor-alpha (TNF-alpha), NO, malondialdehyde (MDA) and superoxide dismutase (SOD) contents in bronchoalveolar lavage fluid (BALF) were measured and the histological appearance of the lung tissue was observed.

RESULTSThe oxygenation index was significantly higher (P<0.05), W/D ratio lower (P<0.05), and contents of TNF-alpha, NO and MAD in the BALF lower in the experimental group than in the control group (P<0.05). The activity of SOD increased significantly in the experimental group as compared with the control group (P<0.01), and the rabbits in the experimental group showed milder pathological changes.

CONCLUSIONIntravenous pentoxifylline may improve pulmonary ventilation function and alleviate pulmonary injury, thus offering protection against pulmonary injury after one-lung ventilation.

Acute Lung Injury ; etiology ; prevention & control ; Animals ; Continuous Positive Airway Pressure ; methods ; Female ; Intubation, Intratracheal ; Male ; Pentoxifylline ; pharmacology ; Pulmonary Ventilation ; Rabbits ; Respiration, Artificial ; adverse effects ; methods