OBJECTIVETo study the effects of alltrans retinoic acid (ATRA) on airway responsiveness, airway remodeling and expression of matrix metalloproteinase-9 (MMP-9) protein in rats with asthma.

METHODSForty rats were randomly divided into five groups: asthma model, normal saline (control), ATRA treatment, cotton oil treatment and budesonide treatment (n=8 each). Asthma was induced by ovalbumin sensitization and challenge in the asthma model, and the ATRA, cotton oil or budesonide treatment groups. ATRA (50 μg/kg), cotton oil (1 mL) or budesonide (0.32 mg/kg) was administered before ovalbumin challenge in the three treatment groups. Airway responsiveness was assessed. The lung tissues were sampled to detect airway remodeling and the expression of MMP-9 protein by immunohistochemistry.

RESULTSThe expression of MMP-9 in lung tissues in the ATRA treatment group was significantly higher than that in the control group, but the airway responsiveness in the ATRA treatment group was not significantly different from that in the control group. The airway responsiveness and the expression of MMP-9 in lung tissues were significantly reduced in the ATRA treatment group compared with the asthma model group. The airway remodeling was significantly improved in the ATRA treatment group compared with the asthma model group.

CONCLUSIONSATRA may alleviate airway hyperresponsiveness and airway remodeling possibly through decreasing the protein expression of MMP-9 in rats with asthma.

Airway Remodeling ; drug effects ; Animals ; Asthma ; drug therapy ; pathology ; physiopathology ; Bronchi ; drug effects ; pathology ; physiopathology ; Lung ; enzymology ; Matrix Metalloproteinase 9 ; analysis ; Rats ; Rats, Sprague-Dawley ; Tretinoin ; pharmacology

OBJECTIVETo investigate the effect of panax notoginseng saponins (PNS) injection on pulmonary artery pressure and the expression of p38MAPK in lung tissue of rats subjected to chronic hypoxia.

METHODSThirty adult male Sprague Dawley rats were randomly divided into three groups (ten in each group): rats in control group were exposed to normoxic condition and the rats in hypoxia group and PNS group were subjected to 4-week hypoxia, and PNS injection (50 mg · kg(-1) · d(-1)) was administrated intraperitoneally at 30 min in the PNS group daily before the rats were kept in the hypoxic chamber, while rats in the other two groups received equal dose of normal saline instead. After chronic hypoxia, mean pulmonary artery pressure (mPAP) and mean carotid artery pressure (mCAP) were measured. The heart and lung tissues were harvested, and right ventricle (RV) and left ventricle plus ventricular septum (LV+S) were weighed to calculate the ratio of RV/(LV+S). The expression of p38MAPK mRNA was determined by reverse transcription-polymerase chain reaction, the quantity of phosphorylated p38MAPK (p-p38MAPK) in rat lung tissues and pulmonary arterioles was determined by Western blot and immunohistochemistry.

RESULTSCompared with the control group, mPAP and the ratio of RV/(LV+S) in the hypoxia group were increased, the expression of p-p38MAPK in pulmonary arterioles and p38MAPK mRNA in the lung were higher (P<0.05). The changes of these parameters in the hypoxia group were significantly attenuated by PNS treatment (P<0.05).

CONCLUSIONPNS injection was shown to prevent hypoxic pulmonary hypertension at least partly by regulating p38MAPK pathway.

Animals ; Arterioles ; drug effects ; metabolism ; Blood Pressure ; drug effects ; Blotting, Western ; Carotid Arteries ; drug effects ; physiopathology ; Disease Models, Animal ; Heart Ventricles ; drug effects ; physiopathology ; Hemodynamics ; drug effects ; Hypertension, Pulmonary ; complications ; enzymology ; physiopathology ; Hypoxia ; complications ; enzymology ; physiopathology ; Injections ; Lung ; drug effects ; enzymology ; pathology ; physiopathology ; MAP Kinase Signaling System ; drug effects ; Male ; Panax notoginseng ; chemistry ; Pulmonary Artery ; drug effects ; physiopathology ; RNA, Messenger ; genetics ; metabolism ; Rats, Sprague-Dawley ; Saponins ; administration & dosage ; pharmacology ; p38 Mitogen-Activated Protein Kinases ; genetics ; metabolism

OBJECTIVETo examine whether pancreatic proteolytic enzymes involve in lung injury induced by trauma/hemorrhagic shock (T/HS).

METHODSMale Sprague-Dawley rats received intraluminal or intravenous pancreatic serine protease inhibitor, 6-amidino-2-naphthyl p-guanidinobenzoate dimethanesulfate (ANGD) during laparotomy (trauma), and were subjected to 90 minutes of T/HS or trauma-sham shock (T/SS). Degree of lung injury was assessed 3 hours after resuscitation with Ringer's lactate solution.

RESULTSLung permeability, pulmonary myeloperoxidase levels and the ratio of bronchoalveolar lavage fluid protein to plasma protein increased after T/HS, and significantly decreased in intraluminal-ANGD treated but not in intravenous-ANGD treated rats. Histological analysis demonstrated fewer injured villi in the intraluminal-ANGD treated rats compared with those in the control rats. Linear regression analysis revealed that the percentage of injured ileal mucosal villi directly related to pulmonary polymorphic neutrophil sequestration and lung permeability to Evans blue dye.

CONCLUSIONSPancreatic proteolytic enzymes in the ischemic gut may be important toxic factors contributing to lung injury after T/HS.

Analysis of Variance ; Animals ; Disease Models, Animal ; Injections, Intralesional ; Injections, Intravenous ; Injury Severity Score ; Laparotomy ; Lung ; drug effects ; pathology ; Lung Injury ; Male ; Probability ; Rats ; Rats, Sprague-Dawley ; Risk Factors ; Sensitivity and Specificity ; Serine Proteinase Inhibitors ; pharmacology ; Shock, Hemorrhagic ; enzymology ; physiopathology

Atelectasis can impair arterial oxygenation and decrease lung compliance. However, the effects of atelectasis on endotoxemic lungs during ventilation have not been well studied. We hypothesized that ventilation at low volumes below functional residual capacity (FRC) would accentuate lung injury in lipopolysaccharide (LPS)-pretreated rats. LPS-pretreated rats were ventilated with room air at 85 breaths/min for 2 hr at a tidal volume of 10 mL/kg with or without thoracotomy. Positive end-expiratory pressure (PEEP) was applied to restore FRC in the thoracotomy group. While LPS or thoracotomy alone did not cause significant injury, the combination of endotoxemia and thoracotomy caused significant hypoxemia and hypercapnia. The injury was observed along with a marked accumulation of inflammatory cells in the interstitium of the lungs, predominantly comprising neutrophils and mononuclear cells. Immunohistochemistry showed increased inducible nitric oxide synthase (iNOS) expression in mononuclear cells accumulated in the interstitium in the injury group. Pretreatment with PEEP or an iNOS inhibitor (1400 W) attenuated hypoxemia, hypercapnia, and the accumulation of inflammatory cells in the lung. In conclusion, the data suggest that atelectasis induced by thoracotomy causes lung injury during mechanical ventilation in endotoxemic rats through iNOS expression.
Animals ; Blood Pressure ; Carbon Dioxide/blood ; Cardiac Output ; Combined Modality Therapy ; Endotoxemia/*complications/immunology/pathology ; Functional Residual Capacity ; Immunohistochemistry ; Leukocytes, Mononuclear/pathology ; Lipopolysaccharides/pharmacology ; Lung/enzymology/pathology/physiopathology ; Lung Compliance ; Lung Volume Measurements ; Male ; Neutrophils/pathology ; Nitric Oxide Synthase Type II/metabolism ; Oxygen/blood ; Positive-Pressure Respiration/*adverse effects ; Pulmonary Atelectasis/*etiology/pathology/*therapy ; Rats ; Rats, Sprague-Dawley ; Thoracotomy/*adverse effects

OBJECTIVETo investigate the role of p38 mitogen-activated protein kinase (MAPK) signal transduction pathway in the acute lung injury of severely burned rats.

METHODSForty-eight adult healthy rats were randomly divided into three groups: sham group, burn control group, and burn + SB203580 group. A third-degree burns over 30% total body surface area rat model was used and pulmonary capillary permeability, lung water content, pulmonary histology and p38 MAPK activity were measured at 24 hours postburn.

RESULTSBurn trauma resulted in increased pulmonary capillary leakage permeability (42.5 +/- 4.7 vs. 12.1 +/- 1.4, P < 0.01), elevated lung water content (P < 0.05), and worsen histologic condition. There was a significant activation of p38 MAPK at 24 hours postburn compared with control. SB203580 inhibited the activation of p38 MAPK, reduced the pulmonary capillary leakage permeability (24.7 +/- 2.9 vs. 42.5 +/- 4.7, P < 0.01), decreased lung water content, and prevented burn-mediated lung injury.

CONCLUSIONThe activation of p38 MAPK is one important aspect of the signaling event that contributes to burn-induced lung injury.

Animals ; Blotting, Western ; Burns ; enzymology ; physiopathology ; Enzyme Activation ; drug effects ; Enzyme Inhibitors ; pharmacology ; Imidazoles ; pharmacology ; Lung ; pathology ; physiopathology ; Male ; Mitogen-Activated Protein Kinases ; antagonists & inhibitors ; metabolism ; physiology ; Pyridines ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Respiratory Distress Syndrome, Adult ; enzymology ; physiopathology ; Signal Transduction ; drug effects ; physiology ; p38 Mitogen-Activated Protein Kinases

The purpose of this study was to investigate the therapeutic effects of small hairpin RNA (shRNA) targeting endothelin-converting enzyme (ECE)-1 in monocrotaline (MCT)-induced pulmonary hypertensive rats. Ninty-four Sprague-Dawley rats were divided into three groups: control (n = 24), MCT (n = 35) and shRNA (n = 35). Four-week survival rate in the shRNA group was significantly increased compared to that in the MCT group. The shRNA group showed a significant improvement of right ventricular (RV) pressure compared with the MCT group. The MCT and shRNA groups also showed an increase in RV/(left ventricle + septum) ratio and lung/body weight. Plasma endothelin (ET)-1 concentrations in the shRNA group were lower than those in the MCT group. Medial wall thickness of pulmonary arterioles were increased after MCT injection and was significantly decreased in the shRNA group. The number of intra-acinar muscular pulmonary arteries was decreased in the shRNA group. The mRNA expressions of ET-1 and ET receptor A (ETA) were significantly decreased in the shRNA group in week 4. The protein levels of ETA were decreased in the shRNA group in week 2. The protein levels of tumor necrosis factor-alpha and vascular endothelial growth factor were decreased in the shRNA group in week 4. In conclusion, the gene silencing with lentiviral vector targeting ECE-1 could be effective against hemodynamic, histopathological and gene expression changes in pulmonary hypertension.
Animals ; Aspartic Acid Endopeptidases/*antagonists & inhibitors/blood/genetics ; Body Weight ; Heart Ventricles/physiopathology ; Hypertension, Pulmonary/chemically induced/*enzymology/mortality ; Lentivirus/genetics ; Lung/anatomy & histology/metabolism/pathology ; Male ; Metalloendopeptidases/*antagonists & inhibitors/blood/genetics ; Monocrotaline/toxicity ; Pulmonary Artery/drug effects/physiopathology ; RNA, Small Interfering/*metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Endothelin A/genetics/metabolism ; Survival Rate ; Tumor Necrosis Factor-alpha/metabolism ; Vascular Endothelial Growth Factor A/metabolism

Although continuous low-dose (metronomic [MET]) therapy exerts anti-cancer efficacy in various cancer models, the effect of long-term MET therapy for hepatocellular carcinoma (HCC) remains unknown. This study assessed the long-term efficacy of MET on suppression of tumor growth and spontaneous metastasis in a rat model of HCC induced by administration of diethylnitrosamine for 16 wk. The rats were divided into 3 groups: MTD group received intraperitoneal (i.p.) injections of 40 mg/kg cyclophosphamide on days 1, 3, and 5 of a 21-day cycle; Control and MET groups received i.p. injections of saline and 20 mg/kg cyclophosphamide twice a week, respectively. Anti-tumor and anti-angiogenic effects and anti-metastatic mechanisms including matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were evaluated. Twelve wk of MET therapy resulted in a significant reduction in intrahepatic tumors than control or MTD therapy. The MET group had fewer proliferating cell nuclear antigen-positive cells and decreased hypoxia-inducible factor-1alpha levels and microvessel density. Lung metastases were detected in 100%, 80%, and 42.9% in the control, MTD, and MET groups, respectively. MET therapy significantly decreased expression of TIMP-1, MMP-2 and -9. For mediators of pro-MMP-2 activation, MET therapy induced significant suppression in the TIMP-2 and MMP-14 level. The survival in the MET group was significantly prolonged compared to the control and MTD groups. Long-term MET scheduling suppresses tumor growth and metastasis via its potent anti-angiogenic properties and a decrease in MMPs and TIMPs activities. These results provide a rationale for long-term MET dosing in future clinical trials of HCC treatment.
Animals ; Antineoplastic Agents/*administration & dosage/*pharmacology ; Carcinoma, Hepatocellular/chemically induced/*drug therapy/mortality/pathology ; Cell Proliferation/drug effects ; Cyclophosphamide/*administration & dosage/*pharmacology ; Diethylnitrosamine ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic/*drug effects ; Liver Cirrhosis/chemically induced ; Liver Neoplasms/chemically induced/*drug therapy/mortality/pathology ; Lung Neoplasms/drug therapy/pathology/secondary ; Male ; Matrix Metalloproteinases/metabolism ; Neovascularization, Pathologic/enzymology/physiopathology ; Rats ; Rats, Sprague-Dawley ; Survival Analysis ; Tissue Inhibitor of Metalloproteinases/metabolism ; Tumor Burden/drug effects