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OBJECTIVE: To explore the role of platelet factor 4 (PF4) and ß-thromboglobulin (ß-TG) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: A total of 71 AECOPD patients and 50 chronic obstructive pulmonary disease (COPD) patients within a stable stage were admitted into Beijing Chaoyang Hospital from January 2008 to June 2010. And another 40 healthy volunteers were selected as control group. The data of demographics, arterial blood gas analysis and pulmonary function parameters was collected and analyzed. The plasma levels of PF4 and ß-TG were measured by enzyme-linked immunosorbent assay (ELISA). Platelet count was measured by hematology analyzer. Statistical analysis was used for PF4, ß-TG and platelet count. Spearman rank correlation was used for correlation analysis. RESULTS: No differences in age and gender existed among the AECOPD, stable and control groups. The plasma level of PF4 in the AECOPD group (2.28 µg/L) was significantly higher than that of the stable group (2.01 µg/L) and control group (1.57 µg/L) (both P < 0.05). The level of ß-TG in AECOPD was 2.32 µg/L and it was significantly higher than that of the stable group (1.85 µg/L) and control group (1.29 µg/L) (both P < 0.05). The differences in platelet counts were insignificant between the AEC OPD group ((196 ± 67) ×10(9)/L), stable group ((194 ± 50) ×10(9)/L) and control group ((190 ± 48) ×10(9)/L). AECOPD group was divided into moderate, severe and very severe groups by pulmonary function parameters. The levels of PF4 and ß-TG in very severe group were significantly higher than those in moderate and severe groups (P < 0.05). A significant positive correlation was observed between PF4 and ß-TG (r = 0.518, P < 0.01). The levels of PF4 and ß-TG were negatively correlated with FEV1%, FEV1/FVC and PaO2 (all P < 0.05). CONCLUSION: Abnormal platelet activation exists in AECOPD. And the levels of PF4 and ß-TG may reflect the severity of AECOPD and can be used as the markers of estimating prethrombotic state.
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Factor Plaquetario 4/sangre , Enfermedad Pulmonar Obstructiva Crónica/sangre , beta-Tromboglobulina/metabolismo , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Plasma/metabolismo , Activación Plaquetaria , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To explore the effects of aerosolized earthworm fibrinolytic enzyme (EFE) on bleomycin-induced pulmonary fibrosis in rats. METHODS: A total of 72 male SD rats were divided randomly into 3 groups of bleomycin (BLM) group with intratracheal BLM (5 mg/kg), control group with the same dose of normal saline, then after both receiving aerosolization of normal saline once daily instead of EFE, EFE group with EFE (2500 U/kg) by aerosolization once daily after BLM instillation. Lung histopathology, immunohistochemistry for transforming growth factor ß(1) (TGF-ß(1)), lung hydroxyproline contents, levels of urokinase PA (uPA), tissue plasminogen activator (tPA) and PA inhibitor 1 (PAI-1) in lung and blood were observed at Days 7, 14 and 28 of experiment, respectively. RESULTS: Compared with BLM group, pulmonary fibrosis improved and the TGF-ß(1) expression of lung tissue decreased (P < 0.01). Hydroxyproline content of lung tissue decreased in EFE group compared with BLM group ((5.8 ± 2.5) vs (9.6 ± 1.3), (6.7 ± 1.4) vs (9.7 ± 1.5), (7.5 ± 1.2) vs (9.7 ± 1.4) mg/L, P < 0.01). Compared with BLM group, the uPA levels of lung were elevated in EFE group at Days 7 and 14 ((1.04 ± 0.36) vs (0.72 ± 0.11), (0.90 ± 0.09) vs (0.75 ± 0.08) µg/L, P < 0.05). Moreover, the plasma levels uPA of increased at Days 14 and 28 ((0.32 ± 0.04) vs (0.25 ± 0.02), (0.36 ± 0.05) vs (0.28 ± 0.04) µg/L, P < 0.05). Consistently, compared with BLM group, the tPA levels of lung increased in EFE group ((4.70 ± 0.87) vs (3.01 ± 0.62), (5.72 ± 0.37) vs (3.00 ± 0.51), (6.73 ± 1.12) vs (3.18 ± 0.38) µg/L, P < 0.01) and the plasma levels of tPA also increased ((3.40 ± 0.36) vs (1.79 ± 0.38), (3.17 ± 0.37) vs (2.18 ± 0.17), (3.85 ± 0.56) vs (2.80 ± 1.06) µg/L, P < 0.01). However, compared with BLM group, the PAI-1 levels of lung decreased in EFE group ((6.04 ± 0.81) vs (8.52 ± 1.01), (6.78 ± 0.81) vs (9.81 ± 1.73), (7.63 + 0.99) vs (11.44 ± 2.54), P < 0.05) and the plasma levels of PAI-1 also decreased in EFE group ((4.82 ± 0.42) vs (6.89 ± 0.84), (5.73 ± 0.40) vs (7.30 ± 1.09), (5.64 ± 0.87) vs (7.98 ± 1.10) µg/L, P < 0.05). CONCLUSIONS: Earthworm fibrinolytic enzyme may decrease bleomycin-induced pulmonary fibrosis and TGF-ß(1) expression while increasing fibrinolytic activation. And fibrinolytic strategies are probably useful for the therapy of fibrotic lung diseases.
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Endopeptidasas/administración & dosificación , Endopeptidasas/farmacología , Fibrosis Pulmonar/metabolismo , Administración por Inhalación , Aerosoles , Animales , Bleomicina/efectos adversos , Masculino , Oligoquetos/enzimología , Inhibidor 1 de Activador Plasminogénico/metabolismo , Fibrosis Pulmonar/inducido químicamente , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
OBJECTIVE: To explore the changes and clinical significances of plasma D-dimer, factor X and tissue factor in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and analyze the in-depth changes of these indicators in AECOPD with co-current deep venous thrombosis (DVT). METHODS: A total of 56 AECOPD patients were divided into the DVT and non-DVT subgroups (n = 28 each). And 60 normal control subjects were recruited according to age and gender. For each subject, 2.7 ml whole blood was drawn and then the plasma levels of D-dimer, factor X and tissue factor were detected. The results were statistically analyzed with the software SPSS 13.0. And the analysis of variance was performed between the groups. RESULTS: There was no significant difference between the distribution of the AECOPD group and the control group by gender and age. Therefore two groups were comparable. And in the AECOPD group, there was no significant difference between the distribution of DVT and non-DVT subgroups by gender and age. Therefore these two subgroups were comparable as well. The value of D-dimer in the AECOPD patients was significantly higher than that in the normal control [(0.76 ± 0.30) vs (0.29 ± 0.11) mg/L, P < 0.01]; and in the AECOPD group, the value of D-dimer in the DVT subgroup was significantly higher than that in the non-DVT subgroup [(0.85 ± 0.29) vs (0.67 ± 0.28) mg/L, P < 0.05]. In the AECOPD group, the value of tissue factor was (238 ± 68) mg/L and the value of factor X (1181 ± 337) mg/L. While in the normal control group, the values were (124 ± 30) and (998 ± 260) mg/L respectively. As for tissue factor and factor X, there were significant differences between two groups (all P < 0.01). Yet in AECOPD patients, neither indicator had significant differences between the DVT and non-DVT subgroups (all P > 0.05). CONCLUSION: The blood of AECOPD patients is in a hypercoagulatory state. And an obvious rise in their plasma level of D-dimer suggests that it may be complicated with DVT.
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Coagulación Sanguínea , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfermedad Aguda , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Factor X/metabolismo , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tromboplastina/metabolismo , Trombosis de la Vena/etiologíaRESUMEN
INTRODUCTION: Endothelium derived nitric oxide (NO) is a key mediator of vascular homeostasis. Endothelial nitric oxide synthase (eNOS) gene, by affecting the expression and functional activity of the eNOS enzyme, thereby reducing NO availability, may be implicated in venous thromboembolism (VTE). We investigated the eNOS G894T polymorphism in VTE patients in the Chinese population. MATERIALS AND METHODS: A case-control study was conducted in a general hospital. Blood samples, collected from 462 consecutive patients with VTE and 462 healthy controls, were used for DNA extraction. Single nucleotide polymorphisms (SNP) of eNOS (894G/T) were determined by allele specific-polymerase chain reaction (ARMS-PCR) analysis. RESULTS: The eNOS 894G/T polymorphism alleles distribution was in agreement with the principle of Hardy-Weinberg equilibrium. The prevalence of homozygote, heterozygote and pathological homozygote for the eNOS G894T polymorphism in VTE patients was 79.7%, 18.1% and 2.2%, respectively (controls: 86.6%ï¼12.3% and 1.1%). T allele distribution in the VTE (11.3%) and especially the male VTE patients (12.5%) was more common than in healthy controls (7.3%). The frequency of GT+TT genotype was significantly higher among the age≤55years patients in VTE group than in controls (20.1% vs. 12.2%, P=0.033). CONCLUSION: Our result demonstrates that the 894G/T polymorphism variant of eNOS is a risk factor for VTE in Chinese population.
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Óxido Nítrico Sintasa de Tipo III/genética , Polimorfismo de Nucleótido Simple , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/genética , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , China/epidemiología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factores Sexuales , Adulto JovenRESUMEN
OBJECTIVE: To investigate the effects of asynchronous independent lung ventilation and synchronous independent lung ventilation with different levels of positive end-expiratory pressure (PEEP) and tidal volumes on hemodynamics and gas exchange in dogs with a hydrochloric acid induced acute lung injury. METHODS: Twelve dogs with hydrochloric acid induced acute lung injury (left lung) were ventilated with volume controlled ventilation (VCV). The animals were randomly divided by random digit table into 2 groups. The first group (group NS, n = 6) received asynchronous independent lung ventilation with the left lung PEEP 10 cm H2O (1 cm H2O = 0.098 kPa), VT 3.5 ml/kg and the right lung PEEP 0 cm H2O, VT 5 ml/kg. The second group (group S, n = 6) received synchronous independent lung ventilation with the parameters as same as group NS. HR, mABP, mPAP, PAWP, CO and blood gas levels were measured during ventilation with different levels of PEEP (15, 20, 25 cm H2O) and VT (5, 7.5, 10 ml/kg) for 30 min. RESULTS: (1) After 30 min ventilation, no significant differences for hemodynamics and gas exchange were found between group NS and group S when Left lung PEEP was 15 or 20 cm H2O and VT was 5 or 7.5 ml/kg. (2) After 30 min ventilation, HR, mABP, CO, PaO2/FiO2, SvO2 in group NS [(98 ± 8) beats/min, (84 ± 6) mm Hg (1 mm Hg = 0.133 kPa), (1.10 ± 0.13) L/min, (199 ± 14) mm Hg and (55 ± 6)%, respectively] were significantly lower than those in group S [(124 ± 9) beats/min, (103 ± 7) mm Hg, (1.52 ± 0.28) L/min, (221 ± 15) mm Hg and (62 ± 4)%, respectively] when PEEP was 25 cm H2O (all P < 0.01). (3) After 30 min ventilation, HR, mABP, CO, PaO2/FiO2, SvO2 in group NS [(92 ± 6) beats/min, (83 ± 9) mm Hg, (1.23 ± 0.08) L/min, (196 ± 8) mm Hg and (57 ± 2)%, respectively] were significantly lower than those in group S [(122 ± 10) beats/min, (104 ± 4) mm Hg, (1.56 ± 0.12) L/min, (216 ± 14) mm Hg and (63 ± 4)%, respectively] when VT was 10 ml/kg (all P < 0.01). CONCLUSIONS: In this animal model, the hemodynamics kept stable when the difference between the left lung PEEP and the right lung PEEP was less than 20 cm H2O. Synchronous independent lung ventilation caused less hemodynamic compromise when higher PEEP (> 25 cm H2O) was used because of the marked asymmetry in the mechanics of the 2 lungs.
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Lesión Pulmonar/fisiopatología , Lesión Pulmonar/terapia , Respiración con Presión Positiva , Ventilación Pulmonar , Volumen de Ventilación Pulmonar , Animales , Modelos Animales de Enfermedad , Perros , Femenino , Hemodinámica , Masculino , Presión Esfenoidal PulmonarRESUMEN
OBJECTIVE: To study the expression of intercellular cell adhesion molecule-1 (ICAM-1), Interleukin-10 (IL-10) and the activation of transcription factor activator protein-1 (AP-1) in a rabbit model of ventilator-induced lung injury (VILI) and therefore to explore their possible role in VILI. METHODS: The VILI model was established by mechanical ventilation with a large tide volum (V(T)) of 40 ml/kg. Forty healthy male New Zealand rabbits were randomly divided into 5 groups: a control group without mechanical ventilation, a conventional ventilation group, and injurious ventilation with large V(T) for 1 h group, 2 h group and 4 h group. The concentrations of soluble ICAM-1 (sICAM-1) and IL-10 in lung homogenates were measured by enzyme-linked immunosorbent assay (ELISA). The level of mRNA was measured by semiquantitative transcription-polymerase chain reaction (RT-PCR). The DNA-binding activity of AP-1 was measured by electrophoretic mobility shift assay (EMSA). The partial arterial blood pressure of oxygen (PaO2), myeloperoxidase (MPO) in lung homogenate, wet lung weight to dry lung weight ratio (W/D) were observed. RESULTS: (1) The concentrations of sICAM-1 in large V(T) for 2 h group (23 ± 5) ng/L and 4 h group (35 ± 5) ng/L were higher than that in the conventional ventilation group (16 ± 4) ng/L (P all < 0.05), and that in the Large V(T) for 4 h group were higher than that in 1 h group (19 ± 4) ng/L and 2 h group (P all < 0.01). The concentrations of IL-10 in the large V(T) for 2 h group (24 ± 4) ng/L and 4 h group (26 ± 5) ng/L were higher than that in the conventional ventilation group (15 ± 2) ng/L (P all < 0.05), and that in the Large V(T) for 4 h group was higher than that in the 1h group (19 ± 4) ng/L(P < 0.05). The level of ICAM-1 mRNA in the large V(T) for 2 h group (1.18 ± 0.19) and 4 h group (1.29 ± 0.19) were higher than that in the conventional ventilation group (0.84 ± 0.13) (P all < 0.05), and that in Large V(T) for 4 h group was higher than that in 1 h group (0.96 ± 0.24) (P < 0.05). The level of IL-10 mRNA in the large V(T) for 4 h group (1.13 ± 0.17) was higher than that in the conventional ventilation group (0.84 ± 0.20) and Large V(T) for 1 h group (0.86 ± 0.12) (P all < 0.05). (2) The DNA-binding activity of AP-1 in the large V(T) for 2 h group (33.77 ± 8.23) and 4 h group (38 ± 9) were higher than that in the conventional ventilation group (23 ± 9) (P all < 0.01), and that in Large V(T) for 4 h group was higher than that in 1h group (25 ± 9) (P < 0.01). (3) Histopathological findings demonstrated that diffused alveolar damage induced by mechanical ventilation was worse with time, and after mechanical ventilation with large V(T) for 2 h, the level of MPO began to increase, and for 4 h the PaO2 reduced and the W/D increased. CONCLUSIONS: ICAM-1 and IL-10 took part in the inflammatory responses of VILI, and their up-regulation maybe due to the increase of their mRNA. Nuclear transcription factor AP-1 maybe involved in the transcriptional regulation mechanisms of these inflammatory mediators.
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Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-10/metabolismo , Factor de Transcripción AP-1/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/metabolismo , Animales , Pulmón/metabolismo , Pulmón/patología , Masculino , ConejosRESUMEN
AIM: To investigate the role of chemokine receptor CXCR3 in cigarette smoking (CS)-induced pulmonary damage. METHODS: CXCR3 knockout (CXCR3-/-) mice were used. Differences in airspace enlargement, mRNA expression of matrix metalloproteinases (MMPs), transforming growth factor (TGF) beta1, CXCL10 in lung homogenates, and CXCL10 content in bronchoalveolar lavage (BAL) fluids and homogenates were compared between CXCR3-/- mice and wild-type (WT) mice three days after three-day CS exposures. RESULTS: The linear intercept was significantly less in CXCR3-/- mice than in WT mice (30.1+/-0.9 microm vs 40.3+/-2.4 microm, P<0.01). Morphologically, collagen was deposited less around airways and vessels in CXCR3-/- mice. The lung hydroxyproline content was significantly lower in CXCR3-/- mice than in WT mice (6.0+/-1.0 microg/mL vs 12.0+/-1.6 microg/mL, P<0.05). Profoundly lower mRNA expression of MMP2, MMP12, TGF beta 1, and CXCL10 was seen in lung homogenates from CXCR3-/- mice. CXCL10 concentrations in BAL fluid and lung homogenates were significantly lower in CXCR3-/- mice than in WT mice (BAL fluid: 19.3+/-1.4 pg/mL vs 24.8+/-1.6 pg/mL, P<0.05; lung homogenates: 76.6+/-7.0 pg/mL vs 119.5+/-15.9 pg/mL, P<0.05). CONCLUSION: CXCR3 is important in mediating lung tissue damage and airway remodeling following a short-term CS insult, possibly through up-regulation of CXCL10 and inducement of mRNA expression of MMPs. Targeting CXCR3 may be helpful for prevention of CS-induced pulmonary pathology.
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Pulmón/patología , Receptores CXCR3/inmunología , Fumar/inmunología , Fumar/patología , Animales , Líquido del Lavado Bronquioalveolar/química , Quimiocina CXCL10/genética , Quimiocina CXCL10/inmunología , Quimiocina CXCL10/metabolismo , Regulación de la Expresión Génica , Pulmón/inmunología , Pulmón/metabolismo , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/genética , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Fumar/metabolismo , Factor de Necrosis Tumoral alfa/análisisRESUMEN
BACKGROUND: Peripheral skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD) may be due to the disease per se or as a result of concomitant confounding factors. Although the mechanistic basis for this functional impairment is uncertain, oxidative stress may play a role. The purpose of this study was to investigate whether local oxidative stress is associated with the reduced peripheral skeletal muscle performance in rats with emphysema. METHODS: In situ mechanical properties of gastrocnemius were measured in Sprague-Dawley rats 5 months after intratracheal instillation of either elastase (EMP, n = 10) or normal saline (CON, n = 10). Lipofuscin inclusions, myocyte apoptosis and antioxidant enzyme activities were examined in the gastrocnemius muscle. RESULTS: Lipofuscin inclusions were significantly higher in the gastrocnemius muscle of EMP compared with CON (3.2 + or - 0.4 vs. 1.7 + or - 0.4, P < 0.01). The activities of antioxidant enzymes were significantly increased in muscle homogenates of EMP as compared to CON. No significant differences were found in myocyte apoptosis between EMP and CON (1.2 + or - 0.9 vs. 1.0 + or - 0.8, P > 0.05). EMP decreased the fatigue endurance of gastrocnemius muscle (half-time to fatigue recovery: (150.0 + or - 55.4) seconds vs. (55.2 + or - 29.3) seconds, P < 0.01) and had no effect on maximal tetanic force ((467.4 + or - 36.6) g vs. (493.2 + or - 30.5) g, P > 0.05). A significantly positive correlation was found between the level of lipofuscin inclusions and the half-time to fatigue recovery of gastrocnemius muscle in EMP (r = 0.664, P < 0.05). CONCLUSION: Local oxidative stress may have important functional consequences for peripheral skeletal muscle in rats with EMP.
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Enfisema/metabolismo , Enfisema/fisiopatología , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Estrés Oxidativo/fisiología , Animales , Catalasa/metabolismo , Enfisema/patología , Técnicas In Vitro , Masculino , Músculo Esquelético/patología , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismoRESUMEN
OBJECTIVE: to explore the effect of simvastatin on alveolar epithelial cells and the expression of vascular endothelial growth factor (VEGF) in cigarette smoking-induced emphysema in rats. METHODS: twenty-four, 12-week-old healthy male and female Wistar rats were randomly divided into 4 groups of 6 each: a control (W) group, a smoking (Sm) group, a simvastatin (St) group, and a smoking-simvastatin (SmSt) group. The rats were simultaneously fed, and kept in individual cages for 16 weeks. The VEGF level in lung tissue and bronchoalveolar lavage fluid (BALF) of each group was measured by ELISA. The expression of VEGF mRNA was determined by RT-PCR. The expressions of VEGF and proliferating cell nuclear antigen (PCNA) were determined by two-step immunohistochemistry assay. One-way ANOVA and LSD-t test were used for statistical analysis. RESULTS: the percentage of PCNA-positively stained alveolar epithelial cells was significantly higher in the SmSt group [(10.3 ± 2.0)%] than in the Sm group [(4.8 ± 0.8)%]. The levels of VEGF in BALF and lung tissue homogenate of the SmSt group [(187 ± 15) ng/L and (6782 ± 50) ng/L] were similar to the W group [(200 ± 20) ng/L and (7558 ± 330) ng/L], but were significantly higher than that in the Sm group [(71 ± 16) ng/L and (4149 ± 110) ng/L]. VEGF expression in alveolar and bronchial epithelial cells of rats in the SmSt group [(67.7 ± 5.0)% and (49.0 ± 3.0)%], was similar to the W group [(68.3 ± 3.3)% and (51.3 ± 2.9)%]. But the level of VEGF expression was significantly increased as compared to that in the Sm group [(27.0 ± 5.9)% and (16.3 ± 2.7)%]. SmSt group vs Sm group t = 1.117 - 12.001, all P < 0.01. CONCLUSIONS: simvastatin ameliorated the development of cigarette smoke-induced COPD in rats, partly by promoting alveolar epithelial cell proliferation and up-regulating the expression of VEGF.
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Células Epiteliales/efectos de los fármacos , Alveolos Pulmonares/efectos de los fármacos , Enfisema Pulmonar/metabolismo , Simvastatina/farmacología , Fumar , Animales , Líquido del Lavado Bronquioalveolar , Proliferación Celular , Femenino , Pulmón/metabolismo , Masculino , Alveolos Pulmonares/citología , Alveolos Pulmonares/metabolismo , Enfisema Pulmonar/inducido químicamente , Ratas , Ratas Wistar , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVE: To establish a model of chronic periodontitis (CP) accompanied with chronic obstructive pulmonary disease (COPD) in SD rats and investigate the relationship between chronic periodontitis and COPD. METHODS: Equal gender SD rats were randomly divided into 4 groups, A: control group, B: CP group, C: COPD group, D: COPD with CP group (n = 10, respectively). Each group was subjected to its predesigned intervention to establish a specific disease model. After 10 weeks, animals were sacrificed. The level of alveolar bone loss, lung function measurement, and the histopathological changes of periodontal and lung tissues were examined. The serum tumor necrosis factor (TNF)-α level was detected by enzyme-linked immunoabsorbent assay kits. RESULTS: Bleeding index (BI) levels of group A and C were (0.25 ± 0.04) and (1.30 ± 0.25), respectively. Attachment loss was (0.43 ± 0.02) and (0.51 ± 0.02) mm. BI levels in group B and D were significantly higher than those in group A and C. Forced expiratory volume in 0.2 second to forced vital capital ratio (FEV(0.2)/FVC) values in group B, C and D were significantly lower than that in group A. Pulmonary function were worse in group D than that in group C (P < 0.05). The levels of serum TNF-α, a sensitive indicator of both diseases, were increased in all test groups compared with the control, and increased most in group D. CONCLUSIONS: The chronic periodontitis and chronic obstructive pulmonary disease model was established in SD rat. The chronic periodontitis may be a risk factor for promoting and inducing COPD.
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Periodontitis Crónica , Modelos Animales de Enfermedad , Enfermedad Pulmonar Obstructiva Crónica , Pérdida de Hueso Alveolar , Animales , Volumen Espiratorio Forzado , Pulmón , Ratas , Factor de Necrosis Tumoral alfaRESUMEN
OBJECTIVE: To explore the mechanism of Chinese medicinal therapy for nourishing blood and softening Gan in treating senile pruritus through observing the impact of Guishen Zhiyang Recipe (GZR) on serum levels of stem cell factor (SCF) and dynorphin (DYN) in patients suffered from the disease of blood-deficiency and Gan-hyperactive syndrome type (BDGH). METHODS: Sixty patients with senile pruritus were equally randomized into two groups, the patients in the treated group (33 cases) were treated by GZR, and those in the control group (28 cases) were treated by Fuyang Granule, all for 8 weeks. Changes of symptoms and skin lesions as well as blood levels of SCF and DYN were observed before and after treatment. RESULTS: Three patients were rejected from the treated group. Twenty patients in the treated group were cured after treatment, the cure rate being 66.7%, which was significantly higher than that in the control group (10 patients, 35.7%, P < 0.05). Levels of SCF and DYN in the treated group significantly lowered after treatment (all P < 0.01), and were lower than those in the control group (P < 0.05 and P < 0.01, respectively). CONCLUSION: GZR shows favorite effect in treating senile pruritus of BDGH type and it may be achieved by regulating SCF and DYN levels to improve the pruritus associated inflammatory media.
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Medicamentos Herbarios Chinos/uso terapéutico , Fitoterapia , Prurito/tratamiento farmacológico , Prurito/metabolismo , Anciano , Anciano de 80 o más Años , Dinorfinas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factor de Células Madre/metabolismo , SíndromeRESUMEN
BACKGROUND: The body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index was shown at predicting the risk of death, exacerbation and disease severity among patients with COPD, but few studies verified relationship between BODE index and health related quality of life (HRQoL) among Chinese COPD patients. The objective of this study was to evaluate the relationship between BODE index and HRQoL in cross-sectional and longitudinal association analyses. METHODS: A multi-center prospective cohort study was initially conducted in 491 stable COPD patients in Beijing, China. Health status (HRQoL) was assessed by St. George's Respiratory Questionnaire (SGRQ); the BODE index was calculated for each patient; dyspnea was assessed using the 5-grade Medical Research Council dyspnea scale. Other measurements included socio-demographic, body mass index (BMI), lung function test and 6-minute-walk test (6MWT). Patients were then followed monthly for 12 months. RESULTS: Only 450 patients completed the 1-year follow up and were enrolled in our present analyses. Mean age was (65.2 +/- 10.6) years, men 309 (68.7%). The BODE index was categorized into 4 subgroups: 0 - 2, 3 - 4, 5 - 6 and 7 - 10. At baseline BODE index was gradually increased with baseline total SGRQ and SGRQ subscales (P trend < 0.001). For individual components of BODE index, with the decrease of airflow limitation, and 6MWD, and with the increase of Medical Research Council (MRC) dyspnea grade, total SGRQ and SGRQ subscales were increased correspondingly, P trend < 0.05, respectively. Similar association patterns were found between baseline BODE index and its individual components and mean SGRQ scores at the end of 1-year follow up. By multiple linear regression analyses, baseline BODE index was not only significantly associated with SGRQ score at baseline but also with SGRQ score at the end of 1-year follow up after adjustment for age, male, current smoking, betas being 0.434 and 0.378, respectively. CONCLUSIONS: BODE index is associated with SGRQ score cross-sectionally and longitudinally among stable COPD patients. BODE index might have potential to be used as a sensitive tool to assess the status of quality of life and to monitor disease progression among stable COPD patients.
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Enfermedad Pulmonar Obstructiva Crónica/patología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Calidad de Vida , Anciano , Índice de Masa Corporal , Estudios Transversales , Disnea/patología , Disnea/fisiopatología , Tolerancia al Ejercicio/fisiología , Femenino , Humanos , Modelos Lineales , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pruebas de Función Respiratoria , Fumar , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To observe the changes of the plasma soluble thrombomodulin (sTM) concentrations in patients with pulmonary thromboembolism (PTE) and assess the association between plasma sTM concentration and the risk of PTE. PATIENTS AND METHODS: We measured plasma concentrations of sTM, protein C (PC) and protein S (PS) and examined the association between those plasma markers and the risk of PTE in 72 selected PTE patients and 70 controls. RESULTS: Significant difference was identified in plasma sTM level between overall PTE patients and controls. Female PTE patients had statistically lower sTM concentrations than male patients. A positive linear correlation was found between plasma sTM concentration and age in female patients. Decreased plasma sTM concentration was associated with a continuously and progressively increased risk for PTE in women. The concentrations of plasma PC and PS did not differ between groups and no significant quantitative association was identified between the risk of PTE and the levels of plasma PC or PS. CONCLUSION: Decreased plasma sTM concentration is associated with an increased risk of PTE in women.
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Embolia Pulmonar/etiología , Trombomodulina/sangre , Adulto , Factores de Edad , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína C/análisis , Proteína S/análisis , Factores de Riesgo , Factores Sexuales , Solubilidad , Adulto JovenRESUMEN
AIM: CXCR3, via binding its specific ligand CXCL10, plays an important role in cigarette smoke (CS)-induced pulmonary inflammation. CXCR3 is preferentially expressed in activated T cells (chiefly CD8+ T cells). The purpose of this study was to investigate the role of CXCR3 in CS-induced pulmonary injury using CXCR3 gene-deficient (CXCR3-/-) mice. METHODS: Differences in the infiltration of inflammatory cells and CD8+ T cells and the expression of inflammatory mediators and chemokines in the bronchoalveolar lavage fluid and lungs at the mRNA and protein levels were compared between CXCR3-/- mice and wild-type (WT) mice at 2 h after 3 d of CS exposure. RESULTS: Compared with their WT counterparts, the CXCR3-/- mice showed alleviated inflammation, as evidenced by fewer inflammatory cells, particularly cytotoxic CD8+ T cells, in bronchoalveolar lavage fluid and lung tissues. At both the mRNA and protein levels, there were significantly lower levels of inflammatory and chemotactic cytokines, including TNF-alpha, interleukin-8, interferon-gamma, transforming growth factor-beta1, and CXCL10 in the CXCR3-/- mice. CONCLUSION: Our data show that CXCR3 is important in recruiting inflammatory cells (particularly CD8+ T cells) into the airways and lungs, as well as initiating inflammatory and fibrotic cytokines release at 2 h following a short-term CS insult. CXCR3 could be a novel target for the treatment of pulmonary inflammation induced by CS.
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Nicotiana/efectos adversos , Neumonía/inmunología , Receptores CXCR3/metabolismo , Humo/efectos adversos , Fumar , Animales , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Linfocitos T CD8-positivos/inmunología , Quimiocina CXCL10/genética , Quimiocina CXCL10/inmunología , Quimiocinas/genética , Quimiocinas/inmunología , Citocinas/genética , Citocinas/inmunología , Humanos , Pulmón/citología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Noqueados , Receptores CXCR3/genéticaRESUMEN
OBJECTIVE: To evaluate protective effect and its mechanism of prone position ventilation (PPV) combined with recruitment maneuver (RM) as a lung protective ventilation strategy on oleic acid-induced acute respiratory distress syndrome (ARDS) in dogs. METHODS: Twenty-four oleic acid-induced ARDS dogs were ventilated with volume controlled ventilation (VCV): 16 cm H2O (1 cm H2O=0.098 kPa) of positive end-expiratory pressure (PEEP) and 10 ml/kg of tidal volume (VT). All dogs were randomly divided by random digit table into four groups: supine position (SP group), prone position (PP group), supine position+RM (SPRM group), and prone position+RM (PPRM group, 6 in each group), and ventilated by VCV for 4 hours and then sacrificed by exsanguination. The serum levels of inflammatory mediators were measured respectively at 0.5, 2 and 4 hours. After they were sacrificed, the levels of cytokines in left lung tissue homogenate were measured. The wet/dry weight ratio of right lung was determined and histological sections of the lungs were prepared and examined. RESULTS: (1) At 4 hours, interleukin-8 (IL-8) in serum in the SPRM group was significantly higher than in other three groups (all P<0.05), tumor necrosis factor-alpha (TNF-alpha) in serum in the SPRM group was significantly higher than in the PP group and the PPRM group (all P<0.05). (2) IL-8 in lung tissue homogenate of the dorsal aspect of the lung in the SP group was higher than in the PP group and the PPRM group (both P<0.05). TNF-alpha in lung tissue homogenate at the dorsal aspect of the lung in the SPRM group was higher than in the PP group and the PPRM group (both P<0.05). (3) Wet/dry weight ratio of right lung in the PP group and the PPRM group were significantly lower than that in the SP group and the SPRM group (all P<0.05). (4)Pathology score of lung tissue at the dorsal aspect of the lung in the PP group and PPRM group was significantly lower than in the SP group and the SPRM group (all P<0.05). CONCLUSION: Protective ventilation strategy combined with RM is safer in prone position than supine position, and it alleviates lung injury in dog with ARDS.
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Posición Prona , Respiración Artificial/métodos , Síndrome de Dificultad Respiratoria/terapia , Animales , Modelos Animales de Enfermedad , Perros , Femenino , Pulmón/patología , Lesión Pulmonar/prevención & control , Masculino , Distribución AleatoriaRESUMEN
OBJECTIVE: To evaluate the effects of prone position ventilation (PPV) combined with recruitment maneuver (RM) on oxygenation and intrapulmonary shunting in oleic acid-induced acute respiratory distress syndrome (ARDS) in canines while ventilated with lung protective ventilation strategy. METHODS: ARDS was induced by oleic acid in 24 dogs, and the animals were ventilated with volume controlled ventilation (VCV), 16 cm H2O (1 cm H2O = 0.098 kPa) of positive end-expiratory pressure (PEEP) and small tidal volumes (V(T) 10 ml/kg). All the dogs were randomly divided by random digit table into 4 groups (6 each), a control group (supine position, SP group), a prone position group (PP group), a supine position + RM group (SPRM group), and a prone position + RM group (PPRM group), and then were ventilated by VCV for 4 h. Arterial and mixed venous blood gas analyses were measured. Data were analyzed using the SPSS for windows (version 11.5). Results were expressed as x +/- s. Homogeneity of variance test was performed. The differences in means were calculated using one-way ANOVA. Post-hoc multiple comparisons of means were performed using Least Significant Difference. Nonparametric tests for several independent samples were performed to compare differences between the ranks in the groups studied. P value of < 0.05 was considered statistically significant. RESULTS: (1) At 15 min, PaO2/FiO2 in the SPRM group, the PP group and the PPRM group [(368 +/- 45) mm Hg (1 mm Hg = 0.133 kPa), (349 +/- 80) mm Hg, ( 423 +/- 43) mm Hg, respectively] was significantly higher than that in the SP group [(269 +/- 72) mm Hg, q = 2.77, 2.23, 4.31, respectively, all P < 0.05]. At 2 h, PaO2/FiO2 in the PP group and the PPRM group [(401 +/- 82) mm Hg, (416 +/- 23) mm Hg, respectively] was significantly higher than that in the SP group [(232 +/- 40) mm Hg, q = 3.99, 4.35, respectively, all P < 0.05]. At 4 h, PaO2/FiO2 in the PPRM group [(384 +/- 68) mm Hg] was significantly higher than that in the SP group [(256 +/- 75) mm Hg], that in the SPRM group [(267 +/-92) mm Hg] and that in the PP group [(284 +/- 83) mm Hg, q = 2.75, 2.56, 2.17, respectively, all P < 0.05]. (2) Intrapulmonary shunt (Q(S)/Q(T)) in the PP group was significantly decreased compared with that in the SP group from 30 min to 2 h [30 min (9.9 +/- 4.4)% vs (15.0 +/- 1.6)%, 1 h (9.7 +/- 4.5)% vs (16.0 +/- 2.0)%, 2 h (8.3 +/- 4.6)% vs (16.2 +/- 1.8)%, q = 2.86, 3.00, 3.65, respectively, all P < 0.05]. The Q(S)/Q(T), in the PPRM group was significantly decreased compared with that in the SP group from 30 min to 4 h [30 min (10.0 +/- 1.0)% vs (15.0 +/- 1.6)%, 1 h (10.4 +/- 2.7)% vs (16.0 +/- 2.0)%, 2 h (10.2 +/- 0.7)% vs (16.2 +/- 1.8)%, 4 h (10.1 +/- 1.1)% vs (15.7 +/- 1.7)%, q = 2.80, 2.67, 2.75, 2.99, respectively, all P < 0.05]. CONCLUSIONS: On the basis of small tidal volume lung and PEEP protective ventilation strategy, combining prone position and recruitment maneuver was more effective and showed a synergistic effect on improving oxygenation and intrapulmonary shunt.
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Respiración con Presión Positiva/métodos , Posición Prona , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/terapia , Animales , Análisis de los Gases de la Sangre , Modelos Animales de Enfermedad , Perros , Femenino , Masculino , Oxígeno/química , Pruebas de Función RespiratoriaRESUMEN
OBJECTIVE: To investigate the effects of nitric oxide (NO) inhalation (iNO) on alveolar liquid clearance (ALC), alveolar permeability, and lung edema, and its possible mechanism. METHODS: Eighteen male rabbits were challenged with endotoxin, and they were randomly assigned into three groups: mechanical ventilator (MV) group [volume control ventilation: tidal volume (V(T)) 15 ml/kg, respiration rate (RR) 40 beats/minute, positive end-expiratory pressure (PEEP): 5 cm H(2)O (1 cm H(2)O=0.098 kPa)], high; NO ( 40 x 10(-6) NO, HNO) group and low concentration; NO (10 x 10(-6) NO, LNO) group. Indexes including haemodynamics, blood gas analysis, and mechanics of breathing were determined after MV at different time points in each group. The rabbits were sacrificed after MV lasting for 4 hours. Wet/dry weight (W/D) ratio of the lung was calculated, and the condition of alveolar exudation was observed. RESULTS: (1) Oxygenation index (PaO(2)/FiO(2)) in HNO group and LNO group were higher than those in MV group at 0.5 hour after treatment. (2) The peak pressure of airway (Ppeak) and plateau pressure of airway (Pplat) in LNO group were lower than those in MV group at 0.5, 2 and 4 hours after treatment (P<0.05 or P<0.01). Ppeak at 4 hours, Pplat at 2 hours and 4 hours were lower in HNO group as compared with those in MV group (P<0.05 or P<0.01). Pplat in LNO group was lower than that in HNO group at 2 hours and 4 hours (both P<0.01). (3) Alveolar exudation in HNO group and LNO group was milder than that in MV group (F=22.756, P<0.01). ALC in HNO group and LNO group were higher than that in MV group (F=3.965, P<0.05). The W/D ratio of lung in MV group was higher than that in HNO group, and the W/D rate in HNO group was higher than that in LNO group (F=11.740, P<0.01). (4) Lung injury score in HNO group and LNO group was higher than that in MV group, but without significant difference. CONCLUSION: iNO can reduce lung edema by increasing ALC and improving alveolar permeability, and the LNO may be more effective than HNO in treatment of early acute lung injury induced by endotoxin.
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Lesión Pulmonar Aguda/metabolismo , Óxido Nítrico/administración & dosificación , Alveolos Pulmonares/metabolismo , Edema Pulmonar/tratamiento farmacológico , Lesión Pulmonar Aguda/complicaciones , Lesión Pulmonar Aguda/patología , Administración por Inhalación , Animales , Modelos Animales de Enfermedad , Endotoxinas/toxicidad , Pulmón/patología , Masculino , Edema Pulmonar/etiología , Conejos , Distribución AleatoriaRESUMEN
BACKGROUND: Sepsis induced acute lung injury (ALI) as a common syndrome in clinical practice has a high mortality. Recombinant human activated protein C (APC) can significantly reduce the mortality of patients with severe sepsis. Several studies have implicated that APC may be protective in ALI. METHODS: Twenty-one rabbits were operatively prepared and randomly divided into sham, control, or APC groups (n = 7 in each group). After a tracheotomy had been performed, ALI was produced in the control and APC groups by infusion of Escherichia coli endotoxin 100 microg/kg per hour intravenously for 1 hour. The sham group received only the vehicle, infusion of 20 ml of 0.9% saline. The rabbits were studied under anesthesia for 6 hours and were ventilated with 40% oxygen. Bovine APC (25 microg x kg(-1) x h(-1)) was intravenously administered. The infusion was initiated half an hour post-injury and lasted for 4 hours. The animals were resuscitated with Ringer's lactate solution. RESULTS: In comparison with nontreatment in the control group, the infusion of APC significantly reduced the increase of thrombomodulin level (TM; control group was (0.68 +/- 0.06) ng/ml, vs APC group of (0.62 +/- 0.07) ng/ml at 6 hours, P < 0.05), and significantly attenuated the fall in protein S (PS; control group was (2.32 +/- 0.03) microg/ml at 2 hours, (2.24 +/- 0.06) microg/ml at 4 hours and (2.21 +/- 0.09) microg/ml at 6 hours, vs APC group (2.46 +/- 0.04) microg/ml at 2 hours, (2.40 +/- 0.05) microg/ml at 4 hours and (2.39 +/- 0.07) microg/ml at 6 hours, P < 0.01). In addition, APC limited the increase in plasminogen activator inhibitor-1 (PAI-1) both in plasma (control group was (0.68 +/- 0.12) ng/ml at 1 hour, (0.84 +/- 0.06) ng/ml at 2 hours, (0.87 +/- 0.08) ng/ml at 4 hours and (0.91 +/- 0.05) ng/ml at 6 hours, vs APC group (0.42 +/- 0.16) ng/ml at 1 hour, (0.43 +/- 0.04) ng/ml at 2 hours, (0.45 +/- 0.09) ng/ml at 4 hours and (0.45 +/- 0.14) ng/ml at 6 hours, P < 0.01) and in bronchoalveolar lavage fluid (at 6 hours: sham, (1.05 +/- 0.05) ng/ml; control, (1.13 +/- 0.06) ng/ml; APC, (1.06 +/- 0.06) ng/ml; P < 0.05). However, APC failed to prevent the decrease in PaO(2)/FiO(2) ratio. APC-treated rabbits showed no significant difference in platelet count and antithrombin but exhibited less D-dimer production than did the controls. Moreover, APC limited the histopathological score of lung injury (2.6 +/- 0.8 in control, vs 1.4 +/- 0.6 in APC group, P < 0.01). CONCLUSION: Anti-coagulation and pro-fibrinolysis activity may be two of the possible mechanisms by which activated protein C attenuated endotoxin-induced ALI.
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Lesión Pulmonar Aguda/inducido químicamente , Coagulación Sanguínea/efectos de los fármacos , Endotoxinas/farmacología , Fibrinólisis/efectos de los fármacos , Proteína C/farmacología , Lesión Pulmonar Aguda/sangre , Animales , Antitrombina III/metabolismo , Presión Sanguínea/efectos de los fármacos , Masculino , Inhibidor 1 de Activador Plasminogénico/sangre , Proteína S/metabolismo , Conejos , Distribución Aleatoria , Trombomodulina/sangreRESUMEN
OBJECTIVES: To investigate the changes of serum enzymes and cardiac troponin I (TnI) in patients with acute pulmonary thromboembolism (PTE). The relationships between these changes and the pulmonary artery pressure, the right ventricular function and the prognosis were evaluated. METHODS: This prospective multi-centre trial included 519 patients with confirmed PTE from 24 collaborating hospitals, with 54 cases of massive PTE, 195 sub-massive PTE and 270 non-massive PTE. Thrombolytic treatment with urokinase or recombinant tissue plasminogen activator (rt-PA) was administered for massive and sub-massive PTE patients; anti-coagulative therapy with unfractionated heparin or low molecular weight heparin was used for non-massive PTE. RESULTS: The values of serum ALT, AST, CPK and LDH before treatment in massive PTE [(74 +/- 33), (88 +/- 40), (157 +/- 75), (419 +/- 264) U/L] were significantly higher than those in sub-massive [(52 +/- 21), (43 +/- 18), (75 +/- 30), (284 +/- 176) U/L] and non-massive cases [(38 +/- 13), (35 +/- 11), (78 +/- 24), (239 +/- 178) U/L] (P < 0.05). The value of serum ALT at day 7 (84 +/- 39 U/L) in the unfractionated heparin sub-group of the non-massive PTE was significantly higher than that (67 +/- 26 U/L) in the low molecular weight heparin sub-group (P = 0.045). Of the 45 cases with high pulmonary pressure > 80 mm Hg (1 mm Hg = 0.133 kPa), 24 (54.4%) cases showed high serum LDH (P = 0.032) and 17 (41.5%) high serum ALT (P = 0.049). Of the 169 cases with right ventricular dysfunction, 68 (40.2%) cases showed high serum LDH (P = 0.049) and 76 (45.5%) high serum ALT (P = 0.037). Of the 48 cases with poor prognosis, 15 (30.8%) cases showed high serum LDH (P = 0.039) and 26 (54.5%) high serum ALT (P = 0.022). Of the 39 cases with TnI > or = 0.07 microg/L, 24 (63.3%) cases were complicated with decreased right ventricular function (P < 0.01) and 8 (24.2%) with poor prognosis (P = 0.034). CONCLUSIONS: The values of serum ALT, AST, CPK, LDH and TnI are increased in acute PTE. Unfractionated heparin results in higher levels of ALT than lower molecular weight heparin. The increase of serum ALT, LDH and TnI is correlated with pulmonary artery pressure, right ventricular function and the prognosis of the PTE. These changes may be useful in the risk stratification of PTE patients.
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Embolia Pulmonar/sangre , Suero/enzimología , Troponina I/sangre , Enfermedad Aguda , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Arteria Pulmonar/fisiopatología , Embolia Pulmonar/fisiopatologíaRESUMEN
OBJECTIVE: To study the effects of bone marrow mesenchymal stem cells (MSC) on pulmonary fibrosis. METHODS: Bone marrow MSC were harvested from 6 week old male SD rats. Forty-eight female SD rats were randomly divided into six groups. The pulmonary fibrosis models were made by intratracheal instillation of bleomycin (5 mg/kg in 0.3 ml normal saline). The normal controls received intratracheal instillation of NS instead of bleomycin. On the 1st and 7th day after bleomycin administration, the rats received MSC infusion or a same amount of phosphate buffer solution (PBS) as controls via the tail vein, respectively. The rats were sacrificed by the 28 day of experiment, and the pathologic changes and hydroxyproline contents of the lung tissues were investigated. The sry gene of Y chromosome was detected by polymerase chain reaction (PCR). RESULTS: For rats receiving MSC on the 1st and 7th day after bleomycin administration, the lung fibrotic scores were 1.0 +/- 0.2 and 1.6 +/- 0.5, respectively, significantly decreased as compared with rats receiving no MSC (2.5 +/- 0.5 & 2.3 +/- 0.8, respectively). The hydroxyproline contents of lung tissue were (83 +/- 17) microg/mg and (96 +/- 20) microg/mg, also significantly decreased as compared with rats receiving no MSCs [(123 +/- 32) microg/mg & (127 +/- 34) microg/mg, respectively]. Earlier administration of MSCs resulted in more significant improvement of lung injury. The sry gene (322 bp) was detected in lungs of female rats receiving MSC on the first day of bleomycin induced lung injury. CONCLUSIONS: MSC may be involved in the repair of lung injury, especially in the early stage. MSCs are effective in preventing bleomycin induced lung injury and fibrosis.