Importance of the field: Chemokines have principally been associated with inflammation due to their role in the control of leukocyte migration, but just over a decade ago chemokine receptors were ...also identified as playing a pivotal role in the entry of the HIV virus into cells. Chemokines activate seven transmembrane G protein-coupled receptors, making them extremely attractive therapeutic targets for the pharmaceutical industry.
Areas covered in this review: Although there are now a large number of molecules targeting chemokines and chemokine receptors including neutralizing antibodies in clinical trials for inflammatory diseases, the results to date have not always been positive, which has been disappointing for the field. These failures have often been attributed to redundancy in the chemokine system. However, other difficulties have been encountered in drug discovery processes targeting the chemokine system, and these will be addressed in this review.
What the reader will gain: In this review, the reader will get an insight into the hurdles that have to be overcome, learn about some of the pitfalls that may explain the lack of success, and get a glimpse of the outlook for the future.
Take home message: In 2007, the FDA approved maraviroc, an inhibitor of CCR5 for the prevention of HIV infection, the first triumph for a small-molecule drug acting on the chemokine system. The time to market, 11 years from discovery of CCR5, was fast by industry standards. A second small-molecule drug, a CXCR4 antagonist for hematopoietic stem cell mobilization, was approved by the FDA at the end of 2008. The results of a Phase III trial with a CCR9 inhibitor for Crohn's disease are also promising. This could herald the first success for a chemokine receptor antagonist as an anti-inflammatory therapeutic and confirms the importance of chemokine receptors as a target class for anti-inflammatory and autoimmune diseases.
Patients with chronic obstructive pulmonary disease (COPD) are particularly vulnerable to hypoxia-induced autonomic dysregulation. Hypoxemia is marked during sleep. In COPD, altitude exposure is ...associated with an increase in blood pressure (BP) and a decrease in baroreflex-sensitivity (BRS). Whether nocturnal oxygen therapy (NOT) may mitigate these cardiovascular autonomic changes in COPD at altitude is unknown.
In a randomized placebo-controlled cross-over trial, 32 patients with moderate-to-severe COPD living <800 m were subsequently allocated to NOT and placebo during acute exposure to altitude. Measurements were done at low altitude at 490 m and during two stays at 2048 m on NOT (3 L/min) and placebo (3 L/min, ambient air) via nasal cannula. Allocation and intervention sequences were randomized. Outcomes of interest were BP, BRS (from beat-to-beat BP measurement), BP variability (BPV), and heart rate.
About 23/32 patients finished the trial per protocol (mean (SD) age 66 (5) y, FEV
62 (14) % predicted) and 9/32 experienced altitude-related illnesses (8 vs 1, p < 0.05 placebo vs NOT). NOT significantly mitigated the altitude-induced increase in systolic BP compared to placebo (Δ median -5.8 95% CI -22.2 to -1.4 mmHg, p = 0.05) but not diastolic BP (-3.5 95% CI -12.6 to 3.0 mmHg; p = 0.21) or BPV. BRS at altitude was significantly higher in NOT than in placebo (1.7 95% CI 0.3 to 3.4 ms/mmHg, p = 0.02).
NOT may protect from hypoxia-induced autonomic dysregulation upon altitude exposure in COPD and thus protect from a relevant increase in BP and decrease in BRS. NOT may provide cardiovascular benefits in COPD during conditions of increased hypoxemia and may be considered in COPD travelling to altitude.
Pulmonary arterial hypertension (PAH) is a major complication of systemic sclerosis (SSc) and screening is recommended for a timely initiation of disease-targeted drug therapy to modify disease ...progression. Patients with SSc-PAH have a better prognosis when detected and treated early. The PAH can occur in all disease stages and subsets of SSc. Regular screening tests, which are indicative for PAH, e.g. echocardiography, diffusion capacity, brain natriuretic protein (BNP) and a 6-min walking test, are recommended to enhance the suspicion, since clinical symptoms are unspecific and occur late in the course of PAH. In patients with suspected PAH, the diagnosis should be confirmed by right heart catheterization. A multidisciplinary approach in expert centres including rheumatologists and respiratory physicians and cardiologists specialized in pulmonary hypertension is mandatory for management of patients with SSc at risk for or with manifest pulmonary arterial hypertension.
The carbonic anhydrase inhibitor acetazolamide stimulates ventilation through metabolic acidosis mediated by renal bicarbonate excretion. In animal models, acetazolamide attenuates acute ...hypoxia-induced pulmonary hypertension (PH), but its efficacy in treating patients with PH due to pulmonary vascular disease (PVD) is unknown.
28 PVD patients (15 pulmonary arterial hypertension, 13 distal chronic thromboembolic PH), 13 women, mean±SD age 61.6±15.0 years stable on PVD medications, were randomised in a double-blind crossover protocol to 5 weeks acetazolamide (250mg b.i.d) or placebo separated by a ≥2 week washout period. Primary endpoint was the change in 6-minute walk distance (6MWD) at 5 weeks. Additional endpoints included safety, tolerability, WHO functional class, quality of life, arterial blood gases, and hemodynamics (by echocardiography).
Acetazolamide had no effect on 6MWD compared to placebo (treatment effect: mean change 95%CI -18 -40 to 4m, p=0.102) but increased arterial blood oxygenation through hyperventilation induced by metabolic acidosis. Other measures including pulmonary hemodynamics were unchanged. No severe adverse effects occurred, side effects that occurred significantly more frequently with acetazolamide vs. placebo were change in taste (22/0%), paraesthesia (37/4%) and mild dyspnea (26/4%).
In patients with PVD, acetazolamide did not change 6MWD compared to placebo despite improved blood oxygenation. Some patients reported a tolerable increase in dyspnoea during acetazolamide treatment, related to hyperventilation, induced by the mild drug-induced metabolic acidosis. Our findings do not support the use of acetazolamide to improve exercise in patients with PVD at this dosing.
NCT02755298
Departments of 1 Pathology and 2 Pharmacology, Johannes Gutenberg University, Mainz, Germany
Submitted 14 June 2004
; accepted in final form 13 September 2004
Long-term treatment with glucocorticoids ...is associated with mild to moderate hypertension. We reported previously that downregulation of endothelial NO synthase (eNOS) expression and activity is likely to contribute to this increase in blood pressure. In the present study, we tested the effects of dexamethasone on the vasodilation of microvascular arterioles using implanted dorsal skin-fold chambers in anesthetized C57BL/6J mice. Experiments were performed on control mice or on mice treated with dexamethasone (0.13 mg/kg of body wt). Endothelium-dependent vasodilation in response to ACh (0.110 µM) was reduced by dexamethasone in a dose-dependent fashion. Comparable inhibition was seen in tissues superfused with 30 µM N G -nitro- L -arginine methyl ester. In contrast, endothelium-independent vasodilation in response to S -nitroso- N -acetyl- D , L -penicillamine (10 µM) was not influenced by either dexamethasone or N G -nitro- L -arginine methyl ester. Levels of eNOS mRNA in murine hearts and NO 2 /NO 3 in serum were suppressed by dexamethasone (down to 63 and 50% of control values, respectively, at 3 mg/kg of body wt) along with a reduction in eNOS protein to 85.6%. Dexamethasone also concentration dependently reduced the expression of the cationic amino acid transporter-1 in murine hearts and cultured endothelial cells. The suppression by dexamethasone of the ACh-induced vasodilation could be partially reversed by dietary L -arginine (50 mg/kg of body wt) and by dietary vitamin C (10 g/kg of diet). We conclude that suppression by dexamethasone of the endothelium-mediated microvascular vasodilation involves several mechanisms including 1 ) downregulation of eNOS, 2 ) downregulation of cationic amino acid transporter-1, and 3 ) generation of reactive oxygen species. The demonstration that L -arginine and vitamin C can partially offset the effects of dexamethasone on microvascular arterioles suggests the potential clinical usefulness of these agents for the reduction of glucocorticoid-induced hypertension.
endothelial nitric oxide synthase; cationic amino acid transporter-1; L -arginine; glucocorticoids; hypertension; reactive oxygen species; intravital microscopy
Address for reprint requests and other correspondence: H.-A. Lehr, Institute of Pathology, Johannes Gutenberg Univ., Medical Center, Langenbeckstrasse 1, D-55101 Mainz, Germany (E-mail: lehr{at}pathologie.klinik.uni-mainz.de )
Related articles in AJP - Heart:
Corrigendum
AJP - Heart 2005 289: H2752.
Full Text
Patients with COPD might be particularly susceptible to hypoxia-induced autonomic dysregulation. Decreased baroreflex sensitivity (BRS) and increased blood pressure (BP) variability (BPV) are markers ...of impaired cardiovascular autonomic regulation and there is evidence for an association between decreased BRS/increased BPV and high cardiovascular risk. The aim of this study was to evaluate the effect of short-term exposure to moderate altitude on BP and measures of cardiovascular autonomic regulation in COPD patients.
Continuous morning beat-to-beat BP was noninvasively measured with a Finometer
device for 10 minutes at low altitude (490 m, Zurich, Switzerland) and for 2 days at moderate altitude (2,590 m, Davos Jakobshorn, Switzerland) - the order of altitude exposure was randomized. Outcomes of interest were mean SBP and DBP, BPV expressed as the coefficient of variation (CV), and spontaneous BRS. Changes between low altitude and day 1 and day 2 at moderate altitude were assessed by ANOVA for repeated measurements with Fisher's exact test analysis.
Thirty-seven patients with moderate to severe COPD (mean±SD age 64±6 years, FEV
60%±17%) were included. Morning SBP increased by +10.8 mmHg (95% CI: 4.7-17.0,
=0.001) and morning DBP by +5.0 mmHg (95% CI: 0.8-9.3,
=0.02) in response to altitude exposure. BRS significantly decreased (
=0.03), whereas BPV significantly and progressively increased (
<0.001) upon exposure to altitude.
Exposure of COPD patients to moderate altitude is associated with a clinically relevant increase in BP, which seems to be related to autonomic dysregulation.
ClinicalTrials.gov (NCT01875133).
Aim.
To assess the influence of concomitant chronic obstructive pulmonary disease (COPD) on the parameters of left ventricular-arterial interaction in patients with ischemic cardiomyopathy (ICMP).
...Material and methods
. We examined 130 patients with ICMP and 42 patients with ICMP and COPD. All patients underwent transthoracic echocardiography using the MyLab 70 (Italy) according standard method, followed by calculation of the left ventricular-arterial interaction and left ventricular (LV) energy. Statistical data processing was performed using the program “Statistica 12.0” (Stat Soft, Inc., USA).
Results.
We found that patients with isolated ICMP and in combination with COPD often have a functional imbalance between the activity of LV and arterial system, as evidenced by an increase in the left ventricular-arterial interaction ratio. The increase in the left ventricular-arterial interaction ratio is due to an insufficient increase in left ventricular stiffness, but not a change in the elastic properties of the arterial system. This is indicated by a pronounced decrease in left ventricular elasticity against the background of the relative constancy of arterial elasticity. At the same time, in patients with ICMP and COPD we detected significantly more severe impairment in the parameters of left ventricular-arterial interaction and LV energy than in isolated pathology.
Conclusion
. The presence of COPD in patients with ICMP allows us to consider it as a significant negatively modifying factor that has a negative impact on the functionality of LV and parameters of left ventricular-arterial interaction.
The interface and electronic structure of thin (20-74 nm) Co3O4(1 1 0) epitaxial films grown by oxygen-assisted molecular beam epitaxy on MgAl2O4(1 1 0) single crystal substrates have been ...investigated by means of real and reciprocal space techniques. As-grown film surfaces are found to be relatively disordered and exhibit an oblique low energy electron diffraction (LEED) pattern associated with the O-rich CoO2 bulk termination of the (1 1 0) surface. Interface and bulk film structure are found to improve significantly with post-growth annealing at 820 K in air and display sharp rectangular LEED patterns, suggesting a surface stoichiometry of the alternative Co2O2 bulk termination of the (1 1 0) surface. Non-contact atomic force microscopy demonstrates the presence of wide terraces separated by atomic steps in the annealed films that are not present in the as-grown structures; the step height of approx 2.7 A corresponds to two atomic layers and confirms a single termination for the annealed films, consistent with the LEED results. A model of the (1X1) surfaces that allows for compensation of the polar surfaces is presented.
Three isozymes of nitric oxide (NO) synthase (EC 1.14.13.39) have been identified and the cDNAs for these enzymes isolated. In humans, isozymes I (in neuronal and epithelial cells), II (in ...cytokine-induced cells), and III (in endothelial cells) are encoded for by three different genes located on chromosomes 12, 17, and 7, respectively. The deduced amino acid sequences of the human isozymes show less than 59% identity. Across species, amino acid sequences for each isoform are well conserved (>90% for isoforms I and III, >80% for isoform II). All isoforms use L-arginine and molecular oxygen as substrates and require the cofactors NADPH, 6(R)-5,6,7,8-tetrahydrobiopterin, flavin adenine dinucleotide, and flavin mononucleotide. They all bind calmodulin and contain heme. Isoform I is constitutively present in central and peripheral neuronal cells and certain epithelial cells. Its activity is regulated by Ca and calmodulin. Its functions include long-term regulation of synaptic transmission in the central nervous system, central regulation of blood pressure, smooth muscle relaxation, and vasodilatation via peripheral nitrergic nerves. It has also been implicated in neuronal death in cerebrovascular stroke. Expression of isoform II of NO synthase can be induced with lipopolysaccharide and cytokines in a multitude of different cells. Based on sequencing data there is no evidence for more than one inducible isozyme at this time. NO synthase II is not regulated by Ca; it produces large amounts of NO that has cytostatic effects on parasitic target cells by inhibiting iron-containing enzymes and causing DNA fragmentation. Induced NO synthase II is involved in the pathophysiology of autoimmune diseases and septic shock. Isoform III of NO synthase has been found mostly in endothelial cells. It is constitutively expressed, but expression can be enhanced, eg, by shear stress. Its activity is regulated by Ca and calmodulin. NO from endothelial cells keeps blood vessels dilated, prevents the adhesion of platelets and white cells, and probably inhibits vascular smooth muscle proliferation.
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