HMGB1 is mechanistically essential in the development of experimental pulmonary hypertension.

Pulmonary hypertension (PH) is a mortal disease featuring pulmonary vascular constriction and remodeling, right heart failure, and eventual death. Several reports showed that high-mobility group box 1 (HMGB1) appears to be critical for the development of PH; the underlying mechanism, however, has not been revealed. Experiments in the present study demonstrated that HMGB1 levels were elevated in the lung tissue and blood plasma of rats after chronic hypoxia exposure and monocrotaline treatment. HMGB1 was originally located within the nucleus and translocated to the cytoplasm of pulmonary artery smooth muscle cells (PASMCs) upon hypoxia exposure, a process that appeared to be mediated by endogenous H2O2. Exposure to HMGB1 mobilized calcium signaling in PASMCs, a response that was attenuated by extracellular Ca2+ removal, Toll-like receptor 4 (TLR4) inhibition by TAK-242, or transient receptor potential channel (TRPC) suppression with 2-aminoethoxydiphenyl borate (2-APB) and SKF-96365. The sustained phosphorylation of the Akt pathway modulated HMGB1-induced migration of PASMCs. The blockage of HMGB1 with glycyrrhizin or anti-HMGB1 neutralizing antibody attenuated lung inflammation and PH establishment in rats after hypoxia exposure and monocrotaline treatment. The above findings reveal the mechanistic importance of HMGB1 in PH through TLR4- and TRPC-associated Ca2+ influx and Akt phosphorylation-driven PASMC migration.

Astragalus Polysaccharides Attenuate Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats.

Astragalus polysaccharides (APS) have been shown to possess a variety of biological activities including anti-oxidant and anti-inflammation functions in a number of diseases. However, their function in pulmonary arterial hypertension (PAH) is still unknown. Rats received APS (200[Formula: see text]mg/kg once two days) for 2 weeks after being injected with monocrotaline (MCT; 60[Formula: see text]mg/kg). The pulmonary hemodynamic index, right ventricular hypertrophy, and lung morphological features of the rat models were examined, as well as the NO/eNOS ratio of wet lung and dry lung weight and MPO. A qRT-PCR and p-I[Formula: see text]B was used to assess IL-1[Formula: see text], IL-6 and TNF-[Formula: see text] and WB was used to detect the total I[Formula: see text]B. Based on these measurements, it was found that APS reversed the MCT-induced increase in mean pulmonary arterial pressure (mPAP) (from 32.731[Formula: see text]mmHg to 26.707[Formula: see text]mmHg), decreased pulmonary vascular resistance (PVR) (from 289.021[Formula: see text]mmHg[Formula: see text][Formula: see text] min/L to 246.351[Formula: see text]mmHg[Formula: see text][Formula: see text][Formula: see text]min/L), and reduced right ventricular hypertrophy (from 289.021[Formula: see text]mmHg[Formula: see text][Formula: see text][Formula: see text]min/L to 246.351 mmHg[Formula: see text][Formula: see text][Formula: see text]min/L) ([Formula: see text]0.05). In terms of pulmonary artery remodeling, the WT% and WA% decreased with the addition of APS. In addition, it was found that APS promoted the synthesis of eNOS and the secretion of NO, promoting vasodilation and APS decreased the MCT-induced elevation of MPO, IL-1[Formula: see text], IL-6 and TNF-[Formula: see text], reducing inflammation. Furthermore, APS was able to inhibit the activation of pho-I[Formula: see text]B[Formula: see text]. In couclusion, APS ameliorates MCT-induced pulmonary artery hypertension by inhibiting pulmonary arterial remodeling partially via eNOS/NO and NF-[Formula: see text]B signaling pathways.

Mitochondrial transplantation attenuates hypoxic pulmonary hypertension.

Mitochondria are essential for the onset of hypoxia-induced pulmonary vasoconstriction and pulmonary vascular-remodeling, two major aspects underlying the development of pulmonary hypertension, an incurable disease. However, hypoxia induces relaxation of systemic arteries such as femoral arteries and mitochondrial heterogeneity controls the distinct responses of pulmonary versus femoral artery smooth muscle cells to hypoxia in vitro. The aim of this study was to determine whether mitochondrial heterogeneity can be experimentally exploited in vivo for a potential treatment against pulmonary hypertension. The intact mitochondria were transplanted into Sprague-Dawley rat pulmonary artery smooth muscle cells in vivo via intravenous administration. The immune-florescent staining and ultrastructural examinations on pulmonary arteries confirmed the intracellular distribution of exogenous mitochondria and revealed the possible mitochondrial transfer from pulmonary artery endothelial cells into smooth muscle cells in part through their intercellular space and intercellular junctions. The transplantation of mitochondria derived from femoral artery smooth muscle cells inhibited acute hypoxia-triggered pulmonary vasoconstriction, attenuated chronic hypoxia-induced pulmonary vascular remodeling, and thus prevented the development of pulmonary hypertension or cured the established pulmonary hypertension in rats exposed to chronic hypoxia. Our findings suggest that mitochondrial transplantation possesses potential implications for exploring a novel therapeutic and preventive strategy against pulmonary hypertension.

Ginsenoside Rb1 attenuates agonist-induced contractile response via inhibition of store-operated calcium entry in pulmonary arteries of normal and pulmonary hypertensive rats.

BACKGROUND: Pulmonary hypertension (PH) is characterized by sustained vasoconstriction, enhanced vasoreactivity and vascular remodeling, which leads to right heart failure and death. Despite several treatments are available, many forms of PH are still incurable. Ginsenoside Rb1, a principle active ingredient of Panax ginseng, exhibits multiple pharmacological effects on cardiovascular system, and suppresses monocrotaline (MCT)-induced right heart hypertrophy. However, its effect on the pulmonary vascular functions related to PH is unknown. METHODS: We examined the vasorelaxing effects of ginsenoside Rb1 on endothelin-1 (ET-1) induced contraction of pulmonary arteries (PAs) and store-operated Ca(2+) entry (SOCE) in pulmonary arterial smooth muscle cells (PASMCs) from chronic hypoxia (CH) and MCT-induced PH. RESULTS: Ginsenoside Rb1 elicited concentration-dependent relaxation of ET-1-induced PA contraction. The vasorelaxing effect was unaffected by nifedipine, but abolished by the SOCE blocker Gd(3+). Ginsenoside Rb1 suppressed cyclopiazonic acid (CPA)-induced PA contraction, and CPA-activated cation entry and Ca(2+) transient in PASMCs. ET-1 and CPA-induced contraction, and CPA-activated cation entry and Ca(2+) transients were enhanced in PA and PASMCs of CH and MCT-treated rats; the enhanced responses were abolished by ginsenoside Rb1. CONCLUSION: Ginsenoside Rb1 attenuates ET-1-induced contractile response via inhibition of SOCE, and it can effectively antagonize the enhanced pulmonary vasoreactivity in PH.

[Three cases of eosinophilichyperplastic lymphogranuloma in children's parotid area].

From March 2009 to October 2009, three pediatric patients with parotid tumor were cured. Preoperative physical examination showed regional swelling in parotid area, the surface skin was in moderate reddish purple, the border was vague, and the swelling was inactive. The patients' IgE were significantly increased. B ultrasound examination demonstrated the focus was an isoecho with ringlike dark band around, which was concluded as bull's-eye sign. Magnetic resonance imaging (MRI) examination indicated a cystic mass between the skin and parotid. Preoperative diagnosis was eosinophilichyperplastic lymphogranuloma (Kimura's disease) and the granuloma was excised by operation. Pathological examination revealed the capillary vessel hyperplasia in local tissue with a plenty of eosinophils and lymphocytes infiltrating. The disease was confirmed. Although the disease is rare, the diagnosis still could be made by preoperative physical examination, laboratory and imaging examinations.

Three cases of eosinophilichyperplastic lymphogranuloma in children's parotid area / 华西口腔医学杂志

From March 2009 to October 2009, three pediatric patients with parotid tumor were cured. Preoperative physical examination showed regional swelling in parotid area, the surface skin was in moderate reddish purple, the border was vague, and the swelling was inactive. The patients' IgE were significantly increased. B ultrasound examination demonstrated the focus was an isoecho with ringlike dark band around, which was concluded as bull's-eye sign. Magnetic resonance imaging (MRI) examination indicated a cystic mass between the skin and parotid. Preoperative diagnosis was eosinophilichyperplastic lymphogranuloma (Kimura's disease) and the granuloma was excised by operation. Pathological examination revealed the capillary vessel hyperplasia in local tissue with a plenty of eosinophils and lymphocytes infiltrating. The disease was confirmed. Although the disease is rare, the diagnosis still could be made by preoperative physical examination, laboratory and imaging examinations.

[Relationship between p53 gene and chromosome 13q14 variations and prognosis in primary intestinal lymphoma].

OBJECTIVE: Some research has shown that primary intestinal lymphoma with the same immunophenotype has different prognosis. It suggests that the prognosis of this disease is not determined by a single factor but may be related to genetic or chromosomal variations. The p53 gene is an important tumor suppressor gene, and 13q14 deletion is a common chromosomal abnormality of lymphocyte proliferation diseases. This study aimed to explore the role of the p53 gene and chromosome 13q14 variations in the assessment of prognosis in primary intestinal lymphoma. METHODS: p53 gene and chromosome 13q14 expression in paraffin sections of 30 cases of primary intestinal lymphoma and 10 cases of lymph node reactive hyperplasia were ascertained using an improved FISH technique. RESULTS: p53 gene deletion was found in 22.7% of patients with primary intestinal lymphoma at stage I-II and in 75.0% of patients at stage III-IV (x2=6.903, p<0.01). The 30 patients with primary intestinal lymphoma were pathologically classified into-mucosa-associated lymphoid tissue (MALT) (n=14) and non-MALT types (n=16). The MALT lymphoma group had significantly lower incidence of p53 gene deletion (14.3% vs 56.3%; x2=5.662, p<0.05). Average survival time in patients with p53 gene deletion was 13.41 months, being shorter than the patients with normal p53 gene (36.1 months) (t=2.637, p<0.05). 13q14 deletion was found in 40.0% of patients with primary intestinal lymphoma, but none of patients with lymph node reactive hyperplasia showed 13q14 deletion. 13q14 deletion was not significantly related to the pathological type and the clinical stage of primary intestinal lymphoma as well as the survival time. There was no significant correlation between p53 gene and 13q14 deletions. CONCLUSIONS: There was a high incidence of p53 gene deletion in patients with non-MALT lymphoma or at stage III-IV. p53 gene deletion is related to a high tumor malignant degree and a poor prognosis, while-chromosome 13q14 variation is not associated with the prognosis in patients with primary intestinal lymphoma.