Molecular pathogenesis of pulmonary arterial hypertension

Recent investigations have suggested that it might be possible to reverse the pathology of pulmonary arterial hypertension (PAH), a disorder that can be rapidly progressive and fatal despite current treatments including i.v. prostacyclin. This review will address the cellular and molecular processes implicated in clinical, genetic, and experimental studies as underlying the pulmonary vascular abnormalities associated with PAH. Emerging treatments are aimed at inducing apoptosis of abnormal vascular cells that obstruct blood flow and at promoting regeneration of "lost" distal vasculature.     

Combination therapy with glucagon-like peptide-1 and gastrin restores normoglycemia in diabetic NOD mice

OBJECTIVE—Glucagon-like peptide-1 (GLP-1) and gastrin promote pancreatic β-cell function, survival, and growth. Here, we investigated whether GLP-1 and gastrin can restore the β-cell mass and reverse hyperglycemia in NOD mice with autoimmune diabetes.RESEARCH DESIGN AND METHODS—Acutely diabetic NOD mice were treated with GLP-1 and gastrin, separately or together, twice daily for 3 weeks. Blood glucose was measured weekly and for a further 5 weeks after treatments, after which pancreatic insulin content and β-cell mass, proliferation, neogenesis, and apoptosis were measured. Insulin autoantibodies were measured, and adoptive transfer of diabetes and syngeneic islet transplant studies were done to evaluate the effects of GLP-1 and gastrin treatment on autoimmunity.RESULTS—Combination therapy with GLP-1 and gastrin, but not with GLP-1 or gastrin alone, restored normoglycemia in diabetic NOD mice. The GLP-1 and gastrin combination increased pancreatic insulin content, β-cell mass, and insulin-positive cells in pancreatic ducts, and β-cell apoptosis was decreased. Insulin autoantibodies were reduced in GLP-1–and gastrin-treated NOD mice, and splenocytes from these mice delayed adoptive transfer of diabetes in NOD-scid mice. Syngeneic islet grafts in GLP-1–and gastrin-treated NOD mice were infiltrated by leukocytes with a shift in cytokine expression from interferon-γ to transforming growth factor-β1, and β-cells were protected from apoptosis.CONCLUSIONS—Combination therapy with GLP-1 and gastrin restores normoglycemia in diabetic NOD mice by increasing the pancreatic β-cell mass and downregulating the autoimmune response.Pancreatic β-cells can regenerate in response to experimental injury in adult animals (1–3) and can increase in humans in response to conditions such as pregnancy (4) and obesity (5). In addition, there is histological evidence of attempts at β-cell regeneration in humans with type 1 diabetes (6,7). Similarly, β-cell proliferation is increased before diabetes onset in NOD mice, an animal model for human type 1 diabetes, but not sufficiently to keep up with the ongoing autoimmune response that decreases the β-cell mass (8). Therefore, therapies directed at stimulating β-cell regeneration in addition to arresting autoimmunity may restore the β-cell mass and reverse type 1 diabetes.Many putative β-cell growth factors have been identified, one of the most promising being glucagon-like peptide-1 (GLP-1), a peptide secreted from intestinal L-cells in response to nutrient ingestion (9). The actions of GLP-1 to stimulate glucose-dependent insulin secretion and inhibit glucagon release, gastric emptying, and food intake (10) have led to its application as a therapy for type 2 diabetes (11). GLP-1 has additional actions that suggest a therapeutic role in conditions with a deficit in β-cell mass. GLP-1 and long-acting GLP-1 receptor agonists, such as exendin-4, increase the β-cell mass in rodents with surgically or chemically induced diabetes through stimulation of β-cell proliferation and islet neogenesis and inhibition of β-cell apoptosis (12–15). Also, GLP-1 (16) and exendin-4 (17) reduce insulitis and protect β-cells in NOD mice when given before diabetes onset. Exendin-4 has also been reported to reverse diabetes in NOD mice; however, this required combination of exendin-4 with immunosuppressive therapy using antilymphocyte serum (18).Gastrin is a gastrointestinal peptide reported to induce β-cell neogenesis from pancreatic exocrine duct cells in rodents (19,20). Combined gastrin and epidermal growth factor (EGF) treatment induces islet regeneration and restores normoglycemia in alloxan-treated mice (21) and ameliorates hyperglycemia after diabetes onset in NOD mice (22). Here, we report that addition of gastrin to GLP-1 treatment restored normoglycemia in acutely diabetic NOD mice by increasing the pancreatic β-cell mass and downregulating the autoimmune response.     

The Hong Kong Society of Rheumatology consensus recommendations for the management of gout

Clinical Rheumatology - Gout is one of the most common noncommunicable diseases in Hong Kong. Although effective treatment options are readily available, the management of gout in Hong Kong remains...     

Nuclear factor-kappaB activation in neonatal mouse lung protects against lipopolysaccharide-induced inflammation

RATIONALE: Injurious agents often cause less severe injury in neonates as compared with adults. OBJECTIVE: We hypothesized that maturational differences in lung inflammation induced by lipopolysaccharide (LPS) may be related to the nature of the nuclear factor (NF)-kappaB complex activated, and the profile of target genes expressed. METHODS: Neonatal and adult mice were injected with intraperitoneal LPS. Lung inflammation was assessed by histology, and apoptosis was determined by TUNEL (terminal deoxynucleotidyl transferase UTP nick-end labeling). The expression of candidate inflammatory and apoptotic mediators was evaluated by quantitative real-time polymerase chain reaction and Western immunoblot. RESULTS: Neonates demonstrated reduced inflammation and apoptosis, 24 hours after LPS exposure, as compared with adults. This difference was associated with persistent activation of NF-kappaB p65p50 heterodimers in the neonates in contrast to early, transient activation of p65p50 followed by sustained activation of p50p50 in the adults. Adults had increased expression of a panel of inflammatory and proapoptotic genes, and repression of antiapoptotic targets, whereas no significant changes in these mediators were observed in the neonates. Inhibition of NF-kappaB activity in the neonates decreased apoptosis, but heightened inflammation, with increased expression of the same inflammatory genes elevated in the adults. In contrast, inhibition of NF-kappaB in the adults resulted in partial suppression of the inflammatory response. CONCLUSIONS: NF-kappaB activation in the neonatal lung is antiinflammatory, protecting against LPS-mediated lung inflammation by repressing similar inflammatory genes induced in the adult.     

细粒棘球蚴重组抗原B的表达提取及其血清学检测初探

用基因工程技术制备出的细粒棘球绦虫重组抗原B（rAgB）表达载体,经诱导表达、亲和层析纯化获得具生物活性的重组蛋白质rAgB,用Western-Blot法检测病人血清。结果显示rAgB敏感性为91．6％（44／48）,特异性为93．8％（30／32）,其中10例泡球蚴（AE）病人及10例肿瘤病人血清均无交叉反应。说明rAgB具有较高的敏感性及特异性,可用于包虫病的常规血清学诊断,rAgB在宿主菌JM109内稳定表达,因此可在实验室内大量制备用于血清学诊断的rAgB。     

泡状棘球蚴病宿主淋巴细胞的变化及意义

目的　为探讨泡状棘球蚴病宿主体内淋巴细胞在免疫调节和发病中的作用。方法　对泡球蚴感染BALB/c小鼠观察至 2 5周 ,在不同时间取脾制备细胞悬液 ,检测CD+ 4 ,CD+ 8细胞数量。对 2 5例泡球蚴病患者和 18例健康人群 ,用FCM分析了CD+ 3 ,CD+ 4 ,CD+ 8,CD+ 19,CD+ 3 8,CD+ 56和HLA -DR+ 细胞的变化。结果　泡球蚴感染BALB/c小鼠后 ,1～ 8周以CD+ 4 细胞为主 ,随后CD+ 4 细胞减少 ,CD+ 8细胞增加 ,2 0周后改变显著 (P <0 0 5 ) ,CD+ 4 /CD+ 8比值迅速倒置。泡状棘球蚴病患者CD+ 3细胞未发生改变 ,CD+ 4 细胞较正常对照组下降 (P <0 0 5 ) ,CD+ 8细胞上升 (P <0 0 5 ) ,使CD+ 4 /CD+ 8比值降低 (P <0 0 5 )。CD+ 56细胞较正常对照组显著性降低 (P <0 0 1) ,CD+ 19,CD+ 3 8和HLA -DR+ 细胞未发生改变 (P >0 0 5 )。结论　泡球蚴感染小鼠前 8周 ,以CD+ 4 细胞反应为主 ,具有保护性免疫。感染后期逐渐以CD+ 8细胞为主 ,使机体呈免疫抑制状态 ,有利于泡球蚴生存。泡状棘球蚴病患者机体呈免疫抑制状态 ,有利于泡状棘球蚴在体内的生长     

Age and sex influence on pulmonary hypertension of chronic hypoxia and on recovery

To study the influence of age and sex on the hemodynamic and structural response of the pulmonary vascular bed to chronic hypobaric hypoxia, "infant" Sprague-Dawley rats from 8 days old and "adult" rats from 9 wk old, each group including both sexes, were exposed to half atmospheric pressure for 1 mo and then allowed to recover in room air for up to 3 mo. During hypoxic exposure, pulmonary artery hypertension (Ppa) developed in all groups. The level of Ppa was similar in both male and female infant and in male adult rats but was significantly lower (P < 0.01) in the female adult rats. After recovery in room air, only partial regression of Ppa had occurred in all groups (P < 0.001). In male and female adult rats, recovery values were similar but infant rats had more residual Ppa than adults (P < 0.001). The structural changes that developed during hypoxia, especially the abnormal presence of muscle in small and peripheral intra-acinar arteries, were more severe in male adult rats compared with female adults (P < 0.01) and in infants of both sexes compared with male adults (P < 0.01). After recovery, residual structural changes were present in all rat groups but were most severe in the infants (P < 0.01).     

Smooth muscle protein 22alpha-mediated patchy deletion of Bmpr1a impairs cardiac contractility but protects against pulmonary vascular remodeling

Vascular expression of bone morphogenetic type IA receptor (Bmpr1a) is reduced in lungs of patients with pulmonary arterial hypertension, but the significance of this observation is poorly understood. To elucidate the role of Bmpr1a in the vascular pathology of pulmonary arterial hypertension and associated right ventricular (RV) dysfunction, we deleted Bmpr1a in vascular smooth muscle cells and in cardiac myocytes in mice using the SM22alpha;TRE-Cre/LoxP;R26R system. The LacZ distribution reflected patchy deletion of Bmpr1a in the lung vessels, aorta, and heart of SM22alpha;TRE-Cre;R26R;Bmpr1a(flox/+) and flox/flox mutants. This reduction in BMPR-IA expression was confirmed by Western immunoblot and immunohistochemistry in the flox/flox group. This did not affect pulmonary vasoreactivity to acute hypoxia (10% O2) or the increase in RV systolic pressure and RV hypertrophy following 3 weeks in chronic hypoxia. However, both SM22alpha;TRE-Cre;R26R;Bmpr1a(flox/+) and flox/flox mutant mice had fewer muscularized distal pulmonary arteries and attenuated loss of peripheral pulmonary arteries compared with age-matched control littermates in hypoxia. When Bmpr1a expression was reduced by short interference RNA in cultured pulmonary arterial smooth muscle cells, serum-induced proliferation was attenuated explaining decreased hypoxia-mediated muscularization of distal vessels. When Bmpr1a was reduced in cultured microvascular pericytes by short interference RNA, resistance to apoptosis was observed and this could account for protection against hypoxia-mediated vessel loss. The similar elevation in RV systolic pressure and RV hypertrophy, despite the attenuated remodeling with chronic hypoxia in the flox/flox mutants versus controls, was not a function of elevated left ventricular end diastolic pressure but was associated with increased periadventitial deposition of elastin and collagen, potentially influencing vascular stiffness.