Enbucrilate ; adverse effects ; therapeutic use ; Female ; Humans ; Hypertension, Portal ; diagnosis ; etiology ; Liver Cirrhosis, Biliary ; drug therapy ; Middle Aged ; Pulmonary Embolism ; chemically induced ; diagnosis ; Sepsis ; chemically induced ; etiology

In the present study, we carried out intratracheal administration of bone marrow-derived mononuclear cells (BM-MNCs) to dehydromonocrotaline (DMCT)-induced canine pulmonary artery hypertension (PH) of rat model to examine the security and feasibility, and the aim was to discuss the mechanism. All animals (n=30) were randomly divided into 3 groups (n=10 in each group), i. e. control group, PH group and BM-MNCs group. Six weeks after the transplantation, the hemodynamic data and right ventricle weight ratio were significantly improved for those in BM-MNCs group compared with those in PH group. The lung mRNA levels of vascular endothelial growth factor (VEGF) were higher, while preproendothelin-1 (ppET-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were lower compared with those in the PH group (P<0. 05). Immunofluorescence and histochemical results confirmed that 6 weeks after the administration, transplanted BM-MNCs were still alive and could differentiate into pulmonary vascular endothelial cells. These results showed that intratracheal administration of BM-MNCs could obviously reduce or even reverse the DMCT induction of PAH process. The mechanism could be explained as that the function was mainly through the paracrine effect to promote renewable and reduce inflammation.
Animals ; Bone Marrow Cells ; cytology ; Cell Transplantation ; methods ; Dogs ; Familial Primary Pulmonary Hypertension ; Female ; Hypertension, Pulmonary ; chemically induced ; therapy ; Leukocytes, Mononuclear ; transplantation ; Male ; Monocrotaline ; analogs & derivatives ; Rats

OBJECTIVEPulmonary hypertension is a proliferative vascular disease characterized by pulmonary vascular structural remodeling. Until now, the pathogenesis of pulmonary hypertension is still not fully understood. Although considerable progress has been made, there is, to date, no cure for advanced pulmonary vascular disease. Recently, a number of studies suggest that endogenous vascular elastase (EVE) play a role in the vascular changes associated with pulmonary hypertension. The purpose of the study was to determine whether an elastase inhibitor might reverse advanced pulmonary vascular disease produced in rats by injection of monocrotaline.

METHODSOne hundred and twenty male Sprague-Dawley rats were used in this study. The rats were divided into three groups: control, model and ZD-0892 groups. In the model and ZD-0892 groups, the rats were subjected to a single subcutaneous injection of monocrotaline (60 mg/kg) in the hind flank, while the rats in control group received an equivalent volume of 0.9% saline. From day 21, the rats in the ZD-0892 and model groups received twice-daily gavage tube feedings of either ZD-0892 at a dose of 240 mg/kg per day or its administration vehicle, while the rats in control group were subjected to an equivalent volume of 0.9% saline. On days 21, 28 and 35 post-injection, the elastolytic activity was measured with a fluorescence microplate reader and pulmonary artery pressure was detected via catheterization. Meanwhile, the lungs were evaluated morphologically, using the barium-gelatin perfusion technique.

RESULTSThe injection of monocrotaline led to severe pulmonary hypertension in rats 21 days later and pulmonary artery elastolytic activity increased remarkably. A 1-week treatment with ZD-0892 resulted in declines in elastase activity. This was associated with significant declines in pulmonary artery pressure, decreases in muscularization of peripheral arteries and reductions in medial hypertrophy. After 2 weeks, elastase activity returned to normal level. Pulmonary artery pressure and structure were normalized.

CONCLUSIONIncreased elastase activity is important in the development of vascular changes and progressive pulmonary hypertension. ZD-0892 can suppress the elastase activity and completely reverse the fatal pulmonary hypertension induced by monocrotaline in rats.

Animals ; Hypertension, Pulmonary ; chemically induced ; drug therapy ; Male ; Monocrotaline ; toxicity ; Pancreatic Elastase ; antagonists & inhibitors ; Pulmonary Artery ; drug effects ; pathology ; physiopathology ; Pyrroles ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Sulfonamides ; pharmacology

Aged ; Antihypertensive Agents ; adverse effects ; Endothelin-1 ; antagonists & inhibitors ; drug effects ; Face ; pathology ; Female ; Humans ; Hypertension, Pulmonary ; drug therapy ; Sulfonamides ; adverse effects ; Telangiectasis ; chemically induced ; diagnosis

OBJECTIVETo study the clinical features and prognosis of pulmonary arterial hypertension associated with dasatinib.

METHODSTo present a case of pulmonary arterial hypertension (PAH) associated with long-term exposure to dasatinib and review the related literatures.

RESULTSA 23-year-old female with chronic myelogenous leukemia was treated with dasatinib at a dosage of 140 mg/d after failure of imatinib treatment and achieved complete cytogenetic response. The patient was presented with exertional dyspnea after 35 months of administration with dasatinib. The electrocardiogram showed right ventricular hypertrophy and right axis deviation; transthoracic Doppler echocardiography documented a reduction in diameters of left heart chambers with normal systolic left ventricular function, right heart chambers and pulmonary trunk dilatation, an estimated pulmonary arterial pressure of 114 mmHg; Computed tomography showed thickened pulmonary artery. PAH related to dasatinib was diagnosed and dasatinib was permanently discontinued. The symptom of dyspnea disappeared quickly after withdrawal of dasatinib. The heart structure and pulmonary arterial pressure completely recovered after 7 months of dasatinib discontinuation.

CONCLUSIONPAH is a rare adverse effect of dasatinib treatment. Echocardiograhpy, as a non-invasive screening test for PAH, should be performed before starting dasatinib treatment and repeated during the administration with dasatinib. Dasatinib should be withdrawn permanently in patients with PAH.

Dasatinib ; Female ; Humans ; Hypertension, Pulmonary ; chemically induced ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; Prognosis ; Pyrimidines ; adverse effects ; Thiazoles ; adverse effects ; Young Adult

OBJECTIVETo observe the effects and related mechanisms of fasudil on monocrotaline-induced pulmonary arterial hypertension (PAH) in rats.

METHODSA total of 56 healthy male Sprague-Dawley rats were randomly divided into 5 groups: 4 weeks control group (N4), 4 weeks PAH group (M4), 8 weeks control group (N8), 8 weeks PAH group (M8), 8 weeks PAH and fasudil group (F8). PAH was induced by subcutaneous injection of monocrotaline (50 mg/kg). Animals in F8 group received intraperitoneal injection of fasudil hydrochloride (15 mg×kg(-1)×d(-1)) from the end of the 4th week to the end of the 8th week. Rats in control groups and PAH groups received equal volume saline injection. Polyethylene catheters were inserted into the RV through the jugular vein for right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) measurements after various treatment protocols. RV hypertrophy index [RV/(LV+S)] was also measured. Arteries of 50 to 150 µm were evaluated for the median wall thickness and wall area by HE staining as follows: percent wall thickness (WT%) = [(medial thickness×2/external diameter)]×100 and percent wall area (WA%) = (wall area/total area)×100%. The mRNA expression of ROCK-1 in lung tissue was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The protein expressions of ROCK-1 and MYPT-1 in lung tissue were analyzed by Western blot and MYPT-1 phosphorylation, respectively.

RESULTSForty-one rats survived and mortality rate was zero in N4, N8 and M4 groups. Survival rate was significantly higher in F8 group compared to M8 group (75.00% vs. 31.25%, P < 0.05). At the end of the 4th week, RVSP [(62.25 ± 3.24) vs. (31.33 ± 2.35) mm Hg(1 mm Hg = 0.133 kPa)], mPAP [(36.38 ± 2.31) vs.(20.32 ± 1.81) mm Hg], [RV/(LV+S)] (0.5648 ± 0.0580 vs. 0.3458 ± 0.0455), WT% [(25.63 ± 5.35)% vs.(13.38 ± 3.45)%], WA% [(60.36 ± 2.51)% vs. (38.42 ± 2.84)%] were all significantly higher in M4 group than in N4 group (all P < 0.01). RVSP [(54.64 ± 4.11) vs. (67.37 ± 4.68) mm Hg], mPAP [(26.25 ± 2.32) vs. (39.83 ± 1.83) mm Hg], and markedly relieve [RV/(LV+S)] (0.3985 ± 0.0210 vs. 0.7600 ± 0.0341), WT% [(15.64 ± 2.81)% vs. (28.26 ± 4.38)%], WA% [(40.35 ± 2.82)% vs. (68.83 ± 1.63)%] were all significantly lower in F8 group than in M8 group (all P < 0.05) while the expression of ROCK-1 mRNA (1.2139 ± 0.1778 vs. 1.6839 ± 0.3251, P < 0.01), and the protein expression of ROCK-1 and MYPT-1 as well as the extent of MYPT-1 phosphorylation were all downregualted in F8 group compared to M8 group (all P < 0.01).

CONCLUSIONSFasudil can effectively reverse the MCT-induced PAH in rats via downregulating ROCK-1 and MYPT-1.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ; analogs & derivatives ; therapeutic use ; Animals ; Disease Models, Animal ; Familial Primary Pulmonary Hypertension ; Hypertension, Pulmonary ; chemically induced ; drug therapy ; Male ; Monocrotaline ; toxicity ; Protein Phosphatase 1 ; metabolism ; Rats ; Rats, Sprague-Dawley ; Treatment Outcome ; rho-Associated Kinases ; metabolism

OBJECTIVETo investigate the effect of vascular endothelial growth factor (VEGF) gene transfer on the bleomycin(BLM)-induced pulmonary hypertension in immature rabbits.

METHODSImmature rabbits were divided into 4 groups; control, BLM, liposome and trans-gene groups. The systolic, diastolic and mean pulmonary artery pressure (PASP, PADP, MPAP) were measured by micro-catheter, the pathological changes and the expression of VEGFmRNA and eNOSmRNA of endothelial cells in pulmonary arteries were evaluated by HE stain and in situ hybridization.

RESULT(1) The PAP of BLM and liposome groups was higher than that of control and trans-gene groups. The PASP was 16.5+/-2.9, 25.2+/-7.0, 24.4+/-6.0 and 18.3+/-2.7 mmHg; the PADP was 8.8+/-4.2, 13.1+/-3.8, 13.7+/-4.6 and 10.2+/-2.6 mmHg; the MPAP was 12.1+/-4.0, 18.4+/-4.7, 18.4+/-5.1 and 14.1+/-2.5 mmHg in control, BLM, liposome and trans-gene groups respectively. (2) The thickness of wall increased and the cavity became narrow, and the thickness index (TI) and area index (AI) increased in middle and small pulmonary arteries of BLM and liposome groups. The TI was 0.52+/-0.16, 0.65+/-0.16, 0.63+/-0.11 and 0.55+/-0.13; and the AI was 0.74+/-0.17, 0.84+/-0.14, 0.85+/-0.08 and 0.79+/-0.12 in control, BLM, liposome and trans-gene groups,respectively. (3) The level of VEGFmRNA and eNOSmRNA expression in pulmonary arterial endothelial cells decreased in BLM and liposome groups. The level of VEGFmRNA and eNOSmRNA expression in trans-gene group was higher than that in BLM and liposome groups, but lower than that in control group. VEGFmRNA was 0.83+/-0.09, 0.45+/-0.11, 0.45+/-0.13 and 0.65+/-0.18; eNOSmRNA was 0.79+/-0.12, 0.45+/-0.12, 0.50+/-0.14 and 0.56+/-0.08 in control, BLM, liposome and trans-gene groups, respectively.

CONCLUSIONVEGF gene transfer in immature rabbits with BLM-induced pulmonary hypertension could attenuate the increasing of PAP and wall thickness in middle and small pulmonary arteries, and increase the level of VEGFmRNA and eNOSmRNA expression in pulmonary arterial endothelial cells.

Animals ; Animals, Newborn ; Bleomycin ; Endothelium ; metabolism ; Gene Transfer Techniques ; Genetic Therapy ; Hypertension, Pulmonary ; chemically induced ; metabolism ; therapy ; Nitric Oxide Synthase Type III ; biosynthesis ; genetics ; Pulmonary Artery ; metabolism ; RNA, Messenger ; biosynthesis ; genetics ; Rabbits ; Vascular Endothelial Growth Factor A ; biosynthesis ; genetics

OBJECTIVETo investigate the protective effects of rutaecarpine (Rut) on right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension (PH).

METHODForty-eight SD rats were fed adaptively for 1 week and then were randomly divided into the following 4 groups (n = 12): normal control group, monocrotaline (MCT) treatment group, MCT treatment with Rut (20 mg/kg)group and MCT treatment with Rut (40 mg/kg) group. PH rats were induced by a single injection of monocrotaline (60 mg/kg, sc) and were administered with Rut (20 or 40 mg/kg/d) for 4 weeks. At the end of experiment, the right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) were monitored via the right jugular vein catheterization into the right ventricle. The ratio of right ventricle (RV) to left ventricle (LV) + septum (S) and the ratio of RV to tibial length were calculated. Right ventricular morphological changes were deserved by HE staining. Masson's trichrome staining was used to display collagen deposition. The total antioxidative capacity (T-AOC) and malondialdehyde (MDA) levels in right ventricle were determined according to the manufacturer's instructions. mRNA and protein expression levels of NOX4, collagen I and collagen III were analyzed by immunohistochemisty, real-time PCR and Western blot.

RESULTSThe results showed that Rut treatment for 4 weeks attenuated RVSP, mPAP and right ventricular remodeling index (RV/LV + S and RV/Tibial length) of PH rats induced by monocrotaline. Furthermore, the right ventricular collagen deposition and collagen I and collagen I expression induced by MCT were both significantly suppressed by Rut. The expression levels of NOX4 and MDA were obviously decreased, while the T-AOC was significantly increased in right ventricular from PH rats treated with Rut.

CONCLUSIONThese results suggested that Rut ameliorates the right ventricular remodeling in rats with PH induced by MCT through down-regulating of NOX4 expression and collagen accumulation.

Animals ; Antioxidants ; metabolism ; Heart Ventricles ; metabolism ; Hypertension, Pulmonary ; chemically induced ; drug therapy ; Indole Alkaloids ; pharmacology ; Male ; Malondialdehyde ; metabolism ; Monocrotaline ; adverse effects ; NADPH Oxidase 4 ; NADPH Oxidases ; metabolism ; Quinazolines ; pharmacology ; Rats ; Ventricular Remodeling ; drug effects

OBJECTIVETo study the effect of genistein on the expression of heme oxygenase-1 (HO-1) in rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT).

METHODSSixty male Sprague-Dawley rats were randomly divided into 4 groups (n=15), namely the control group, model group, low-dose (20 µg/kg) genistein group and high-dose (80 µg/kg) genistein group. The hemodynamic parameters were measured and the remodeling of pulmonary small arteries was observed by electron microscope (EM). The expression of HO-1 in the lung tissues were detected by Western blotting.

RESULTSCompared with the model group, genistein treatment significantly reduced the elevated mean pulmonary arterial pressure, improved the right ventricular hypertrophy index, and increased the expression of HO-1 in a dose-dependent manner.

CONCLUSIONGenistein attentuates pulmonary arterial hypertension in MCT-treated rats possibly by up-regulation of HO-1 in the lung tissues.

Animals ; Genistein ; pharmacology ; therapeutic use ; Heme Oxygenase (Decyclizing) ; metabolism ; Hypertension, Pulmonary ; chemically induced ; drug therapy ; enzymology ; Lung ; enzymology ; pathology ; Male ; Monocrotaline ; Rats ; Rats, Sprague-Dawley ; Up-Regulation ; drug effects

OBJECTIVETo investigate the role of angiotensin converting enzyme inhibitor (ACEI) in the treatment of acute respiratory distress syndrome (ARDS).

METHODSChanges in physiological and biochemical indexes, and circulating endothelial cells (CEC) were observed in rats of oleic acid-induced ARDS with ACEI-Captopril (Cap) therapy and controls, respectively.

RESULTSUnder the normal systemic blood pressure, Captopril therapy showed good effect on ARDS in rats. Two hours after administration of Captopril, their pulmonary arterial pressure reduced to (14.43 +/- 1.51) mm Hg (1 mm Hg = 0.133 kPa), approximating to normal level, from (23.50 +/- 5.79) mm Hg. The number of CEC, which reflected injuries in pulmonary capillaries, decreased to (4.25 +/- 0.20)/0.9 micro l from (6.88 +/- 1.90)/0.9 micro l. Value of oxygen pressure in arterial blood (PaO(2)) increased to (70.48 +/- 9.54) mm Hg from (35.08 +/- 4.59) mm Hg. In the mean time, ratio of wet to dry lung weight was returned to nearly normal. So, it indicated that high-dose of oleic acid could only induce mild lung injury, and the development of ARDS was obviously inhibited by ACEI.

CONCLUSIONSACEI may effectively depress pulmonary arterial hypertension, block the development of ARDS, and have certain good protective effect on pulmonary capillary endothelia.

Acute Disease ; Angiotensin-Converting Enzyme Inhibitors ; therapeutic use ; Animals ; Captopril ; therapeutic use ; Disease Models, Animal ; Endothelium, Vascular ; drug effects ; physiopathology ; Hypertension, Pulmonary ; complications ; drug therapy ; Male ; Oleic Acid ; Rats ; Rats, Wistar ; Respiratory Distress Syndrome, Adult ; chemically induced ; etiology ; prevention & control