Natriuretic peptides and genesis of asthma: an emerging paradigm?

Exposure to allergens and infections contribute to early immune development. However, knowledge of the role of cellular metabolic, physiologic, and endocrinologic factors in controlling immune development and asthma is limited. Immune cells, including macrophages, dendritic cells, and T lymphocytes, express receptors for atrial natriuretic peptide (ANP) both in the fetal and neonatal lymphoid organs. ANP has garnered much attention for its cardiovascular effects, but its apparently significant role in the physiology and immunity of the lung has been underappreciated. Studies indicate that ANP also plays a significant role in shaping the early immune responses to environmental antigens. The C-terminal prohormone natriuretic peptide ANP (or NP(99-126)), which possesses bronchodilatory properties, is involved in polarizing dendritic cells to produce a T(H)2 response. Also, de novo overexpression of another pro-ANP peptide, NP(73-102), provides persistent bronchoprotection and induces significant anti-inflammatory activities in the lung epithelial cells. Thus natriuretic peptides appear to play a pivotal role in the genesis and control of asthma, and they might provide an important target to modulate allergen-induced immune responses in allergic patients.     

Brain natriuretic peptide

Plasma levels of various neurohumoral factors are activated and have an important role of the pathophysiology of congestive heart failure (CHF). Atrial natriuretic peptide (ANP) and brain (or B-type) natriuretic peptide (BNP) are secreted from cardiomyocytes in response to atrial or ventricular wall stretch. The natriuretic peptides have a fundamental role in cardiovascular remodeling, volume homeostasis, and the response to myocardial injury. Clinical investigations of these peptides have focused on their diagnostic usefulness for heart failure and left ventricular dysfunction and their prognostic usefulness after acute coronary syndromes and heart failure. In patients with left ventricular systolic dysfunction, a high plasma BNP level is an independent prognostic predictor of CHF patients, suggesting that the compensatory activity of the cardiac natriuretic peptide system is attenuated as mortality increases in chronic CHF patients with high plasma levels of ANP and BNP. BNP is more useful than ANP for diagnosis and management of CHF. Recently, rapid BNP assay is available in our country, rapid measurement of BNP in the emergency department may improve the evaluation and treatment of patients with acute dyspnea and thereby reduced the time to discharge and the total cost of treatment. In addition, BNP-guided treatment of heart failure may reduce total cardiovascular events, and delayed time to first event combination with intensive clinically guided treatment.     

Complement regulates inhalation tolerance at the dendritic cell/T cell interface

Pulmonary exposure to innocuous aeroallergens is a common event leading to inhalation tolerance. Distinct subsets of pulmonary dendritic cells (DC) and regulatory T cells (T(Reg)) play critical roles in mediating and maintaining such tolerance. In asthmatics, the same aeroallergens drive a maladaptive, Th2-biased immune response resulting in airway inflammation and airway hyper-reactivity. The mechanisms underlying the breakdown of inhalation tolerance, leading to the Th2-driven inflammation in rising numbers of asthmatic patients from industrialized countries remain elusive. The recent resurgence of interest in the role of the innate immune mediators in regulating adaptive immune response has sparked studies aimed at identifying the role of complement in allergic asthma. In this context, an unexpected role for the anaphylatoxin C5a receptor in allergic sensitization has been found. In models of experimental allergic asthma, ablation of C5aR signaling during initial allergen exposure either induced or enhanced Th2 sensitization. Mechanistically, C5aR signaling directly affected the function of distinct pulmonary DC subsets that induce or control allergen-induced adaptive immune responses. Signaling pathways downstream of C5 may also impact the function of T(Reg), as T(Reg) from C5 sufficient, but not from C5 deficient mice, suppress DC activation and subsequent development of Th2-driven inflammation. The emerging paradigm is that constitutive local generation of C5a and C5aR signaling in airway DCs controls inhalation tolerance directly as well as indirectly through sensitization of airway DCs for T(Reg)-mediated immunosuppression.     

利钾尿肽与心钠素摩尔比在老年原发性高血压中的作用

目的:探讨利钾尿肽(KP)与心钠素摩尔比变化在老年原发性高血压发病中的意义。方法:用放射免疫分析方法测定老年高血压患者血浆、老年自发性高血压大鼠(SHR)血浆及心房和心室组织的KP和心钠素(ANP)含量。结果:高血压患者血浆KP、ANP水平与对照组比较无显著差异。但是,KP与ANP的摩尔比显著低于对照组(P＜0.05),SHR血浆KP、ANP水平显著高于对照组(WKY)(P＜0.01和P＜0.05),KP/ANP摩尔比则显著低于WKY(P＜0.01)。SHR心房KP含量高于心室(P＜0.05),但与对照组WKY比较无显著差异。结论:KP含量及KP与ANP的比例关系的改变,在老年原发性高血压发病中起着一定的作用。     

Atrial natriuretic peptide gene transfer by means of intranasal administration attenuates airway reactivity in a mouse model of allergic sensitization

Atrial natriuretic peptide (ANP) is a bronchodilator; however, the short half-life of ANP in vivo limited its therapeutic utility to treat asthma. The efficacy of intranasally administered plasmid DNA-expressing ANP (pANP; amino acid 99-126; Acc. No. XM131840) on the prevention of allergen-induced airway hyperresponsiveness (AHR) was examined in this study by using a mouse model of asthma. Ovalbumin-sensitized mice were treated with pANP versus control plasmids, and AHR was monitored after ovalbumin challenge for 5 weeks on 10-day intervals starting 4 days after gene transfer. Mice administered pANP demonstrated significantly less AHR for 20 days after treatment. The results demonstrate that pANP gene transfer protects against AHR and might be useful in the treatment of asthma.     

Atrial natriuretic peptide in bronchial asthma.

Regulation of ion transport across the airway mucosa may be involved in the mechanisms producing hyperreactivity and asthma. Atrial Natriuretic Peptide (ANP) has been proposed to participate in the pathogenesis of asthma, and it has been found to have a bronchodilatory effect on asthmatic patients. Experimental evidences suggest that ANP also has some effect on fluid accumulation in the lungs. We hypothesise that ANP may also play a role in the pathogenesis of asthma through changes in the transport of water and ions across the airway epithelium.     

Atrial natriuretic peptide in human urine

Summary A highly sensitive radioimmunoassay to measure atrial natriuretic peptide (ANP) concentration in urine has been established, and its clinical usefulness is presented. ANP in urine was stable at 4° C for several days and was easily measured by our radioimmunoassay. The average ANP excretion in 65 healthy persons was 25.0±1.4 ng/day (mean ± SEM) and the fractional excretion of ANP was 0.7±0.05%. In 14 patients with congestive heart failure, the average ANP excretion was 119.2±29.4 ng/day, which decreased to 53.3±11.0 after successful treatment.Abbreviations ANP atrial natriuretic peptide - hANP human atrial natriuretic peptide - RIA radioimmunoasay - NSB non specific bound - FE_ANP the fractional excretion of atrial natriuretic peptide - FE_Na the fractional excretion of sodium - SIADH the syngrome of inappropriate secretion of antidiuretic hormone     

Toll‐like receptor 4 agonists adsorbed to aluminium hydroxide adjuvant attenuate ovalbumin‐specific allergic airway disease: role of MyD88 adaptor molecule and interleukin‐12/interferon‐γ axis

Background Epidemiological and experimental data suggest that bacterial lipopolysaccharides (LPS) can either protect from or exacerbate allergic asthma. Lipopolysaccharides trigger immune responses through toll‐like receptor 4 (TLR4) that in turn activates two major signalling pathways via either MyD88 or TRIF adaptor proteins. The LPS is a pro‐Type 1 T helper cells (Th1) adjuvant while aluminium hydroxide (alum) is a strong Type 2 T helper cells (Th2) adjuvant, but the effect of the mixing of both adjuvants on the development of lung allergy has not been investigated. Objective We determined whether natural (LPS) or synthetic (ER‐803022) TLR4 agonists adsorbed onto alum adjuvant affect allergen sensitization and development of airway allergic disease. To dissect LPS‐induced molecular pathways, we used TLR4‐, MyD88‐, TRIF‐, or IL‐12/IFN‐γ‐deficient mice. Methods Mice were sensitized with subcutaneous injections of ovalbumin (OVA) with or without TLR4 agonists co‐adsorbed onto alum and challenged with intranasally with OVA. The development of allergic lung disease was evaluated 24 h after last OVA challenge. Results Sensitization with OVA plus LPS co‐adsorbed onto alum impaired in dose‐dependent manner OVA‐induced Th2‐mediated allergic responses such as airway eosinophilia, type‐2 cytokines secretion, airway hyper‐reactivity, mucus hyper production and serum levels of IgE or IgG1 anaphylactic antibodies. Although the levels of IgG2a, Th1‐affiliated isotype increased, investigation into the lung‐specific effects revealed that LPS did not induce a Th1 pattern of inflammation. Lipopolysaccharides impaired the development of Th2 immunity, signaling via TLR4 and MyD88 molecules and via the IL‐12/IFN‐γ axis, but not through TRIF pathway. Moreover, the synthetic TLR4 agonists that proved to have a less systemic inflammatory response than LPS also protected against allergic asthma development. Conclusion Toll‐like receptor 4 agonists co‐adsorbed with allergen onto alum down‐modulate allergic lung disease and prevent the development of polarized T cell‐mediated airway inflammation.     

Cardiac natriuretic peptide hormones during artificial cardiac pacemaker stimulation and left heart catheterization

Summary Brain natriuretic peptide (BNP) is synthesized and released predominantly in the ventricular myocardium whereas atrial natriuretic peptide (ANP) is produced mainly in the atria. This study evaluated whether artificial pacemaker stimulation or left heart catheterization results in specific changes in BNP and ANP plasma levels. Both BNP and ANP responded sensitively to changes in pacemaker stimulation (single-chamber pacemakers; pacing rates of 72 and 92/min) and during the left heart catheterization procedure. However, whereas higher pacing resulted in a more pronounced increase in plasma BNP levels, a stronger ANP release followed catheterization. This incongruous rise in ANP and BNP plasma concentrations points to at least partly independent mechanisms govering the release of BNP and ANP.Abbreviations ANP atrial natriuretic peptide - BNP brain natriuretic peptide     

树突细胞与哮喘Th1/Th2失衡

特应性哮喘患者以Th2免疫反应为主,导致气道炎症,Th1／Th2失衡是特庆性哮喘重要的免疫病理机制,树突细胞（DCs）中肺部主要抗原递呈细胞,不但可以介志对吸入抗原初始的免疫反应,活化辅助性T细胞,而且在可以决定T细胞的分化方向,维持哮喘Th2免疫反应和Th1／Th2失衡机制中发挥重要作用而日益受到重视。本文就近年来对特应性哮喘免疫病理机制中DCs对Th1／Th2失衡影响认识作一综述。     

Mechanism of bronchoprotective effects of a novel natriuretic hormone peptide

BACKGROUND: The natriuretic hormone peptide (NHP)(99-126), a C-terminal peptide of pro-atrial natriuretic factor (proANF), induces bronchodilatory effects in people with asthma. Recently, another plasmid-encoded C-terminal peptide, pNHP(73-102), was shown to induce a long-lasting bronchoprotective effect in a mouse model of allergic asthma. OBJECTIVE: This study was carried out to determine the role of lung epithelial cells in the bronchoprotective and anti-inflammatory activity of these peptides. METHODS: Human type II alveolar epithelial cells (A549) and normal human bronchial epithelial (NHBE) cells were transfected with pNHP(73-102) to test the effect of this peptide on activation of these cells. After transfection, cells were analyzed for changes in Ca(++) and nitric oxide (NO) levels. Also, activation of NFkappaB and the extracellularly regulated kinase (ERK) 1, 2 signaling pathway was examined by luciferase reporter assay and phosphorylation studies respectively. RESULTS: Analysis of intracellular Ca(++) levels in pNHP(73-102) -transfected A549 or NHBE showed that the peptide increases release. This Ca(++) release was accompanied by an increase in the production of NO. Also, overexpression of pNHP(73-102), but not pVAX control, in phorbol myristate acetate-activated A549 cells resulted in a significant decrease in expression of a cotransfected nuclear factorkappaB (NFkappaB)-luciferase reporter. Similarly, pNHP(73-102) decreased TNF-alpha-induced NFkappaB activation in NHBE cells. Furthermore, NHP(73-102) but not atrial natriuretic peptide decreased phosphorylation of Erk-1, 2 in A549 cells. CONCLUSIONS: Overexpression of pNHP(73-102) in epithelial cells causes increased production of intracellular Ca(++) and NO, with a concomitant decrease in activation of NFkappaB and ERK1, 2. These results suggest a bronchodilatory and anti-inflammatory activity of this peptide.     

心房钠尿肽在产科领域的研究进展

心房钠尿肽是一种具有强大的利钠、利尿、扩张血管作用的肽类激素,在胎盘和胎膜组织有丰富的表达,对维持妊娠期间正常的子宫胎盘循环和胎儿生长发育中起重要作用。目前研究发现,心房钠尿肽与妊娠期高血压疾病、胎儿生长受限、胎儿宫内窘迫等一些产科疾病关系密切。心房钠尿肽浓度变化对于这些疾病的诊断、治疗、及预后判断均起一定的作用。不久的将来,心房钠尿肽作为一种药物在临床的应用将越来越广。     

Changes in atrial natriuretic peptide and brain natriuretic peptide associated with hypobaric hypoxia-induced pulmonary hypertension in rats

Experimental pulmonary hypertension induced in a hypobaric hypoxic environment (HHE) is characterized by structural remodeling of the heart and pulmonary arteries. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) both have diuretic, natriuretic, and hypotensive effects, and both are involved in cardiovascular homeostasis as cardiac hormones. To study the effects of HHE on the natriuretic peptide synthesis system, 170 male Wistar rats were housed in a chamber at the equivalent of the 5500-m altitude level for 1-12 weeks. After 1 week of HHE, pulmonary arterial pressure was significantly raised, and the ratio of left ventricle plus septum over right ventricle of the heart showed a significant decrease (compared with those of ground-level control rats). In both ventricular tissues, the expression of ANP messenger (m)RNA and BNP mRNA increased after exposure to HHE. The amounts of ANP and BNP had decreased significantly in right atrial tissue at 12 weeks of HHE (compared with those of the controls), whereas in ventricular tissues at the same time point, both levels had increased significantly. In in situ hybridization and immunohistochemical studies, the staining of the mRNAs for ANP and BNP and of ANP and BNP themselves was more intense in both ventricular tissues after exposure to HHE than before (i.e., in the controls). The results suggest that, in response to HHE, the changes in ventricular synthesis are similar for ANP and BNP. These changes may play a role in modulating pulmonary hypertension in HHE. However, under our conditions, pulmonary hypertension increased progressively throughout the HHE period.     

Preventive and therapeutic effects of oral tolerance in a murine model of asthma

Allergic asthma is an inflammatory disease of the airways, and Th2 cells secreting IL-4 and IL-5 play a pivotal role in its pathogenesis. We have previously demonstrated that oral tolerance can be induced and maintained more profoundly in a Th2-related immune response, and that an ongoing immune response can be suppressed by the oral administration of antigen combined with an appropriate feeding regimen. In the present study, we examined the preventive and therapeutic effects of the oral administration of allergen on a Th2-mediated immune disorder using a murine model of asthma. Our results show that the development of asthma can be blocked completely by orally administering allergen. Airway hyperreactivity, allergen-specific IgE production, Th2-derived cytokines, allergen-induced T cell proliferation and the infiltration of inflammatory effector cells into the lung were prevented by such oral administration. To assess the therapeutic effects of oral administration on the progression of asthma, we tested the effects of oral tolerance in an established asthma model, and found that a multiple high dose-feeding regimen was effective at suppressing the progression of mild asthma. In the high dose-feeding group, the number of eosinophils in bronchoalveolar lavage fluid was reduced and airway reactivity also decreased. However, this was insufficient to reduce airway reactivity and eosinophilia in bronchoalveolar lavage fluid in cases of severe asthma. These results demonstrate that allergic asthma may be ameliorated by feeding allergen; there is hope that these results will provide a new immunotherapeutic strategy for allergic asthma.     

Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation

Atrial fibrillation is a common arrhythmia that is hereditary in a small subgroup of patients. In a family with 11 clinically affected members, we mapped an atrial fibrillation locus to chromosome 1p36-p35 and identified a heterozygous frameshift mutation in the gene encoding atrial natriuretic peptide. Circulating chimeric atrial natriuretic peptide (ANP) was detected in high concentration in subjects with the mutation, and shortened atrial action potentials were seen in an isolated heart model, creating a possible substrate for atrial fibrillation. This report implicates perturbation of the atrial natriuretic peptide-cyclic guanosine monophosphate (cGMP) pathway in cardiac electrical instability.     

The goat mammary gland as a target organ for atrial natriuretic peptide

Milk secretion represents a major route for electrolyte and water excretion in the dairy goat. The aims of this study were to investigate whether the mammary gland is a target site for atrial natriuretic peptide (ANP) in the goat and whether ANP affects mammary sodium and water secretion. Receptor autoradiography using ¹²⁵I-ANP as radioligand revealed specific binding sites in the secretory tissue of the mammary gland. The radioligand was totally displaced by unlabelled ANP, but not by brain natriuretic peptide or the ANP fragment c-ANP_4–23, indicative of ANP-A receptor preference. To elucidate the role of ANP in milk secretion, ANP (30 ng kg^?1min^?1; 120 min) or 0.15 m NaCl (control) were administered in vivo. The ANP infusions caused haemoconcentration, but did not change milk flow or the concentrations of sodium, potassium, lactose, fat and protein in the milk. The results show that the mammary gland of the goat expresses ANP-specific binding sites, however, a physiological role of ANP in goat mammary gland function remains to be elucidated.     

Immunomodulatory and cytoprotective function of atrial natriuretic peptide

The atrial natriuretic peptide (ANP) was described as a peptide hormone synthesized and secreted by heart atria. It plays an important role in the regulation of volume homeostasis; however, the functions of ANP are not restricted to cardiovascular effects. The biological profile of ANP is much broader than originally thought. This article focuses on the immunomodulatory and anti-inflammatory functions of ANP addressing; for example, the influence of ANP on macrophage functions. Another important aspect of ANP reviewed here is its cytoprotective potential. The beneficial effect of ANP in preventing cell damage caused by ischemia and reperfusion warrants special attention. The therapeutic potential of ANP in organ preservation could be important for transplantation medicine.     

Atrial natriuretic peptide in peripheral organs other than the heart

Summary The heart atria represent the major site of synthesis of atrial natriuretic peptide (ANP) in mammals including man, and its function as a regulator of water and salt homeostasis has been repeatedly suggested. However, more recently ANP has been located in organs not intimately related to cardiovascular physiology, e.g. the adrenals, lungs, and gut, as well as tissues belonging to the lymphatic, reproductive or endocrine systems. Thus, ANP might serve many more physiological roles than originally thought, but the functional significance of ANP in these non-cardiac tissues is presently poorly understood.Abbreviations ANP atrial natriuretic peptide - IR-ANP immunoreactive atrial natriuretic peptide - LH luteinizing hormone - ACTH adrenocorticotrophic hormone - RP-HPLC reverse phase high pressure liquid chromatography - mRNA messenger ribonucleic acid - RIA radioimmunoassay - CNS central nervous system     

Mechanisms of mechanical load-induced atrial natriuretic peptide secretion: role of endothelin, nitric oxide, and angiotensin II

There are three members in the natriuretic peptide hormone family, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, brain natriuretic peptide), and C-type natriuretic peptide (CNP), that are involved in the regulation of blood pressure and fluid homeostasis. CNP is found principally in the central nervous system and vascular endothelial cells while ANP and BNP are cardiac hormones. ANP is synthesized mainly in the atria of the normal adult heart, while BNP is produced by both the atria and ventricles. The mechanisms controlling ANP release have been the subject of intense research, and are now fairly well understood. The major determinant of ANP secretion is myocyte stretch. Although much less is known about the factors regulating BNP release from the heart, myocyte stretch has also been reported to stimulate BNP release from both atria and ventricles. However, whether wall stretch acts directly or via factors such as endothelin-1, nitric oxide, or angiotensin II liberated in response to distension has not been established. Recent studies show that by stimulating endothelin type A receptors endothelin plays an important physiological role as a mediator of acute-volume load-induced ANP secretion from atrial myocytes in conscious animals. In fact, endogenous paracrine/autocrine factors liberated in response to atrial wall stretch rather than direct stretch appears to be responsible for activation of ANP secretion in response to volume load, as evidenced by almost complete blockade of ANP secretion during combined inhibition of endothelin type A/B and angiotensin II receptors. Furthermore, under certain experimental conditions angiotensin II and nitric oxide may also exert a significant modulatory effect on stretch-activated ANP secretion. The molecular mechanisms by which endothelin-1, angiotensin II, and nitric oxide synergistically regulate stretch-activated ANP release are yet unclear.     

胃癌中ANP表达与BMP信号通路相互作用对细胞侵袭、转移的影响

目的探讨心房钠尿肽(atrial natriuretic peptide,ANP)在胃癌组织和细胞中的表达及ANP对胃癌细胞侵袭转移的作用。方法采用免疫组化EnVision法检测60例胃癌组织及正常胃黏膜组织中ANP的表达;培养胃癌细胞MGC-803,并将其分为两组:加入ANP组(ANP阳性组)、未加入ANP组(ANP阴性组)。采用Transwell实验检测两组胃癌细胞MGC-803的侵袭性,利用CCK8法检测两组胃癌细胞MGC-803的增殖能力。采用Western blot法检测两组胃癌细胞MGC-803中BMP信号通路相关蛋白表达量的变化及Ki-67、MMP-2和MMP-9蛋白表达量的变化。结果免疫组化检测ANP定位于胃黏膜细胞的胞质中,且在胃癌组织中的阳性率明显低于正常胃组织,差异有统计学意义(P<0.05);CCK8法、Transwell实验结果显示,ANP阳性组胃癌细胞的增殖速度及侵袭性比ANP阴性组低,差异有统计学意义(P均<0.05)。Western blot法检测ANP阳性组中BMP信号通路相关蛋白Smad1/5表达量比ANP阴性组低,差异有统计学意义(P<0.05);BMP6/7和p-Smad1/5的表达升高,差异有统计学意义(P均<0.05)。Western blot法检测ANP阳性组中Ki-67、MMP-2和MMP-9蛋白比ANP阴性组低,差异有统计学意义(P均<0.05)。结论胃癌组织中ANP的表达低于正常胃组织,ANP可能通过激活BMP信号通路抑制胃癌细胞MGC-803的增殖、侵袭和转移,为胃癌的发病机制及靶向治疗提供新思路。