Increased length-dependent activation of human engineered heart tissue after chronic α1A-adrenergic agonist treatment: testing a novel heart failure therapy.

Chronic stimulation of cardiac α1A-adrenergic receptors (α1A-ARs) improves symptoms in multiple preclinical models of heart failure. However, the translational significance remains unclear. Human engineered heart tissues (EHTs) provide a means of quantifying the effects of chronic α1A-AR stimulation on human cardiomyocyte physiology. EHTs were created from thin slices of decellularized pig myocardium seeded with human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and fibroblasts. With a paired experimental design, EHTs were cultured for 3 wk, mechanically tested, cultured again for 2 wk with α1A-AR agonist A61603 (10 nM) or vehicle control, and retested after drug washout for 24 h. Separate control experiments determined the effects of EHT age (3-5 wk) or repeat mechanical testing. We found that chronic A61603 treatment caused a 25% increase of length-dependent activation (LDA) of contraction compared with vehicle treatment (n = 7/group, P = 0.035). EHT force was not increased after chronic A61603 treatment. However, after vehicle treatment, EHT force was increased by 35% relative to baseline testing (n = 7/group, P = 0.022), suggesting EHT maturation. Control experiments suggested that increased EHT force resulted from repeat mechanical testing, not from EHT aging. RNA-seq analysis confirmed that the α1A-AR is expressed in human EHTs and found chronic A61603 treatment affected gene expression in biological pathways known to be activated by α1A-ARs, including the MAP kinase signaling pathway. In conclusion, increased LDA in human EHT after chronic A61603 treatment raises the possibility that chronic stimulation of the α1A-AR might be beneficial for increasing LDA in human myocardium and might be beneficial for treating human heart failure by restoring LDA.NEW & NOTEWORTHY Chronic stimulation of α1A-adrenergic receptors (α1A-ARs) is known to mediate therapeutic effects in animal heart failure models. To investigate the effects of chronic α1A-AR stimulation in human cardiomyocytes, we tested engineered heart tissue (EHT) created with iPSC-derived cardiomyocytes. RNA-seq analysis confirmed human EHT expressed α1A-ARs. Chronic (2 wk) α1A-AR stimulation with A61603 (10 nM) increased length-dependent activation (LDA) of contraction. Chronic α1A-AR stimulation might be beneficial for treating human heart failure by restoring LDA.

The rapid assembly of an elliptical galaxy of 400 billion solar masses at a redshift of 2.3.

Stellar archaeology shows that massive elliptical galaxies formed rapidly about ten billion years ago with star-formation rates of above several hundred solar masses per year. Their progenitors are probably the submillimetre bright galaxies at redshifts z greater than 2. Although the mean molecular gas mass (5 × 10(10) solar masses) of the submillimetre bright galaxies can explain the formation of typical elliptical galaxies, it is inadequate to form elliptical galaxies that already have stellar masses above 2 × 10(11) solar masses at z ≈ 2. Here we report multi-wavelength high-resolution observations of a rare merger of two massive submillimetre bright galaxies at z = 2.3. The system is seen to be forming stars at a rate of 2,000 solar masses per year. The star-formation efficiency is an order of magnitude greater than that of normal galaxies, so the gas reservoir will be exhausted and star formation will be quenched in only around 200 million years. At a projected separation of 19 kiloparsecs, the two massive starbursts are about to merge and form a passive elliptical galaxy with a stellar mass of about 4 × 10(11) solar masses. We conclude that gas-rich major galaxy mergers with intense star formation can form the most massive elliptical galaxies by z ≈ 1.5.

Intense star formation within resolved compact regions in a galaxy at z = 2.3.

Massive galaxies in the early Universe have been shown to be forming stars at surprisingly high rates. Prominent examples are dust-obscured galaxies which are luminous when observed at sub-millimetre wavelengths and which may be forming stars at a rate of 1,000 solar masses (M(middle dot in circle)) per year. These intense bursts of star formation are believed to be driven by mergers between gas-rich galaxies. Probing the properties of individual star-forming regions within these galaxies, however, is beyond the spatial resolution and sensitivity of even the largest telescopes at present. Here we report observations of the sub-millimetre galaxy SMMJ2135-0102 at redshift z = 2.3259, which has been gravitationally magnified by a factor of 32 by a massive foreground galaxy cluster lens. This magnification, when combined with high-resolution sub-millimetre imaging, resolves the star-forming regions at a linear scale of only 100 parsecs. We find that the luminosity densities of these star-forming regions are comparable to the dense cores of giant molecular clouds in the local Universe, but they are about a hundred times larger and 10(7) times more luminous. Although vigorously star-forming, the underlying physics of the star-formation processes at z approximately 2 appears to be similar to that seen in local galaxies, although the energetics are unlike anything found in the present-day Universe.

Phytoextraction of heavy metals by willows growing in biosolids under field conditions.

Biosolids produced by sewage treatment facilities can exceed guideline thresholds for contaminant elements. Phytoextraction is one technique with the potential to reduce these elements allowing reuse of the biosolids as a soil amendment. In this field trial, cuttings of seven species/cultivars of Salix(willows) were planted directly into soil and into biosolids to identify their suitability for decontaminating biosolids. Trees were irrigated and harvested each year for three consecutive years. Harvested biomass was weighed and analyzed for the contaminant elements: As, Cd, Cu, Cr, Hg, Pb, Ni, and Zn. All Salix cultivars, except S. chilensis, growing in soils produced 10 to 20 t ha(-1) of biomass, whereas most Salix cultivars growing in biosolids produced significantly less biomass (<6 t ha(-1)). Salix matsudana (30 t ha(-1)) and S. × reichardtii A. Kerner (18 t ha(-1)) had similar aboveground biomass production in both soil and biosolids. These were also the most successful cultivars in extracting metals from biosolids, driven by superior biomass increases and not high tissue concentrations. The willows were effectual in extracting the most soluble/exchangeable metals (Cd, 0.18; Ni, 0.40; and Zn, 11.66 kg ha(-1)), whereas Cr and Cu were extracted to a lesser degree (0.02 and 0.11 kg ha(-1)). Low bioavailable elements, As, Hg, and Pb, were not detectable in any of the aboveground biomass of the willows.

Diagnosis of Alagille syndrome-25 years of experience at King's College Hospital.

OBJECTIVE: The aim of the study was to study the clinical and histological features of Alagille syndrome (AGS) at presentation comparing the value of the various modalities before the implementation of genetic diagnosis. PATIENTS AND METHODS: We performed a retrospective analysis of the records of 117 children diagnosed as having AGS after referral to King's College Hospital between 1980 and 2005. RESULTS: Cholestasis was seen in 104 of 117 (89%), characteristic facies in 91 of 117 (77%), posterior embryotoxon in 72 of 117 (61%), butterfly vertebrae in 44 of 117 (39%), heart disease (most often peripheral pulmonary stenosis) in 107 of 117 (91%), and renal disease in 27 of 117 (23%). Serum cholesterol levels of >5 mmol/L were seen in 52 of 86 (60.4%). Liver biopsy showed characteristic features of paucity of interlobular bile ducts in 59 of 77 (76.6%) children younger than 16 weeks of age, in 10 of 14 (71.4%) between 16 weeks and 1 year of age, and in 8 of 12 (66.66%) older than 1 year of age. Other biopsy findings were those of nonspecific hepatitis and biliary features. Iminodiacetic acid scans showed no excretion of isotope into the bowel after 24 hours in 21 of 35 (60%), and small/no gallbladder on ultrasound was seen in 29 of 104 (27.8%). Eleven of 117 (9.4%) had a diagnostic laparotomy and operative cholangiography, 2 proceeding to Kasai portoenterostomy before referral to our unit. CONCLUSIONS: Clinical features of AGS are not as consistently informative as suggested in the literature. Hypercholesterolaemia is nonspecific but may be a helpful pointer. Histology is not characteristic in 25%; hepatobiliary iminodiacetic acid scan and ultrasound may suggest a false diagnosis of biliary atresia in 60% and 28%, respectively, supporting the concept that infants with liver disease warrant early referral to a specialist centre. The advent of genetic diagnosis will redefine the syndrome with likely effects on the prognosis of the defined group.

Characterization of foliar manganese (Mn) in Mn (hyper)accumulators using X-ray absorption spectroscopy.

Plant hyperaccumulation of the essential nutrient manganese (Mn) is a rare phenomenon most evident in the Western Pacific region, and differs from hyperaccumulation of other elements. Mn hyperaccumulators employ a variety of species-dependent spatial distribution patterns in sequestering excess foliar Mn, including primary sequestration in both nonphotosynthetic and photosynthetic tissues. This investigation employed synchrotron X-ray absorption spectroscopy (XAS) in a comparative study of Mn (hyper)accumulators, to elucidate in situ the chemical form(s) of foliar Mn in seven woody species from Australia, New Caledonia and Japan. Foliar Mn was found to predominate as Mn(II) in all samples, with strong evidence of the role of carboxylic acids, such as malate or citrate, as complexing ligands. Overall, the X-ray absorption near-edge spectroscopy (XANES) and extended X-ray absorption fine-structure spectroscopy (EXAFS) data appeared weighted against previous observations that oxalate binds excess Mn in Mn-(hyper)accumulating species.

Cadmium tolerance and accumulation in cultivars of a high-biomass tropical tree (Averrhoa carambola) and its potential for phytoextraction.

Averrhoa carambola is a high-biomass tropical tree that has been identified as a Cd accumulator. In the present study, field survey, pot, and hydroponic experiments were conducted to investigate the variation of Cd tolerance and accumulation in cultivars of A. carambola as well as its potential for phytoextraction. In the field survey, it was found that concentrations of Cd in aerial tissues of A. carambola varied greatly among sites and cultivars. The Cd bioconcentration factors (BCFs) and Cd removals by the field-grown A. carambola differed significantly among sites but not among cultivars. Nonetheless, all four carambola cultivars investigated were able to accumulate considerably high concentrations of Cd in their shoots, which indicated that the 4-yr-old carambola stands could remove 0.3 to 51.8% of the total Cd content in the top 20-cm soil layer. When cultured in Cd-spiked soils, the carambola cultivar Hua-Di always showed higher Cd tolerance than the other cultivars; however, this tendency was not confirmed by hydroponic experiment. The Cd BCFs of cultivar Thailand grown in soils with 6 and 12 mg Cd kg(-1) were highest among cultivars, whereas this trend was reversed at 120 mg Cd kg(-1) treatment. Nevertheless, the pot- and hydroponics-grown carambola cultivars generally showed higher capacities to tolerate and accumulate Cd, compared with the control species. The present results indicate that a strong ability to tolerate and accumulate Cd seems to be a trait at the species level in A. carambola, although some degree of variances in both Cd tolerance and accumulation exists among cultivars.

Tolerance and accumulation of lead in Vetiveria zizanioides and its effect on oil production.

Experiments were conducted to evaluate lead tolerance and accumulation in vetiver grass Vetiveria zizanioides (L.), grown in hydroponics and a pot study and to examine the effect of lead on vetiver oil production. Elevated concentrations of lead decreased the length of shoots and roots of plants. However, vetiver grown in highly contaminated soils showed no apparent phytotoxicity symptoms. Lead concentrations in the shoots and roots of vetiver plants grown in hydroponics were up to 144 and 19530 mg kg(-1) and those grown in soil were 38 and 629 mg kg(-1), respectively. Lead had an effect on vetiver oil production and composition by stimulating oil yield and the number of its constituents. Oil yield ranged from 0.4-1.3%; the highest yields were found in plants grown in nutrient solution with 100 mg Pb l(-1) for 5 weeks (1.29%) and 7 weeks (1.22%). The number of total constituents of vetiver oil also varied between 47-143 compounds when lead was presentin the growth medium. The highest number (143) was found in plants grown in soil spiked with 1000 mg Pb kg(-1). The predominant compound was khusimol (10.7-18.1%) followed by (E)-isovalencenol (10.3-15.6%). Our results indicated that lead could increase the oil production of vetiver.

Recurrent acute liver failure and mitochondriopathy in a case of Wolcott-Rallison syndrome.

A 10-year-old Arabic boy of consanguineous parents has suffered eight episodes of acute liver failure with haemolysis triggered by intercurrent febrile illnesses. The first crisis occurred at 9 months of age, after which diabetes mellitus developed. By the age of 6 years, short stature, mild myopathy and later skeletal epiphyseal dysplasia also became evident. His psychosocial development and educational achievements have remained within normal limits. While there were no clear biochemical indicators of a mitochondrial disorder, an almost complete deficiency of complex I of the respiratory chain was demonstrated in liver but not in fibroblast or muscle samples. Molecular analysis of the eukaryotic translation initiation factor 2alpha kinase gene (EIF2AK3) demonstrated a homozygous mutation, compatible with a diagnosis of Wolcott-Rallison syndrome (WRS). This patient's course adds a new perspective to the presentation of WRS caused by mutations in the EIF2AK3 gene linking it to mitochondrial disorders: recoverable and recurrent acute liver failure. The findings also illustrate the diagnostic difficulty of mitochondrial disease as it cannot be excluded by muscle or skin biopsy in patients presenting with liver disease. The case also further complicates the decision-making process for liver transplantation in cases of acute liver failure in the context of a possible mitochondrial disorder. Such patients may be more likely to recover spontaneously if a mitochondrial disorder underlies the liver failure, yet without neurological features liver transplantation remains an option.

The effect of nitrogen form on rhizosphere soil pH and zinc phytoextraction by Thlaspi caerulescens.

The phytoextraction of Zn may be improved by applying N fertilizers to increase the biomass and Zn content of shoots. Rhizosphere-pH change from uptake of different N forms will affect Zn phyto-availability in the rhizosphere and Zn phytoextraction. This glasshouse study examined the effect of N form on Zn phytoextraction by Thlaspi caerulescens (Prayon). The plants were grown in a Zn-contaminated soil (total Zn 250 mg kg-1 soil; pHwater 5.7) and supplied with (NH4)2SO4, Ca(NO3)2 or urea [(NH2)2CO]. The form was maintained by applying the nitrification inhibitor dicyandiamide. A biodegradable chelator ethylenediaminedisuccinic acid (EDDS) was included for comparison. The addition of N doubled the shoot biomass. The highest shoot Zn content occurred in the Ca(NO3)2 treatment and was associated with the highest rhizosphere pH. The lowest shoot dry weight occurred in the EDDS treatment. The Zn concentration in the shoots increased as the rhizosphere pH increased. A significant correlation occurred between Ca and Zn concentrations in the shoots. This study demonstrated that Ca(NO3)2 is a more effective treatment than , urea or EDDS for enhancing Zn phytoextraction in a mildly acidic soil.

Mesangial cell apoptosis: the major mechanism for resolution of glomerular hypercellularity in experimental mesangial proliferative nephritis.

Increases in mesangial cell number may herald glomerular scarring, but they are not irreversible. This study sought mechanisms by which surplus glomerular mesangial cells can be cleared. A small proportion of cultured mesangial cells exhibited typical morphological features of apoptosis (programmed cell death), which was increased by growth factor deprivation or exposure to cycloheximide, stimuli known to increase apoptosis in other cell types. Apoptosis was confirmed by typical internucleosomal chromatin cleavage. In vivo, clear morphological evidence of mesangial apoptosis leading to phagocytosis by neighboring mesangial cells was obtained in self-limited mesangial proliferation induced in rats by Thy1.1 antibody, apoptosis occurring approximately 10-fold more frequently than in the healthy rat glomerulus. Indeed, changes in glomerular cell number in Thy1.1 nephritis strongly suggested that apoptosis is the major cell clearance mechanism counterbalancing cell division, thereby mediating resolution of glomerular hypercellularity in experimental mesangial proliferation.

Nickel and other metal uptake and accumulation by species of Alyssum (Brassicaceae) from the ultramafics of Iran.

Some plants growing on serpentine (ultramafic) soils are able to hyperaccumulate nickel in their above-ground parts. The genus Alyssum L. contains the greatest number of Ni-hyperaccumulator plants so far reported. There are substantial areas of serpentine soils at many locations in Iran. This paper presents the analyses for Ni, Cr, Mn, Fe, Mg and Ca in soils and Alyssum species from the ultramafics of west and northwest Iran. Soil analysis for total elements in these areas indicates that typical concentrations of Ni, Cr, Mn, Fe, Mg and Ca are up to about 1240, 365, 800, 51,150, 152,390 and 11,790 microg g(-1), respectively. During this study, seven Alyssum species were collected. Analysis of leaf dry matter shows that Alyssum bracteatum can contain up to 2300 microg Nig(-1), while the other species contain much lower concentrations of Ni and other elements. A. bracteatum is endemic to Iran and the first Ni hyperaccumulator reported from this species.

Uptake and accumulation of arsenic by 11 Pteris taxa from southern China.

A field survey was conducted at a deserted arsenic (As) mine in Guangxi Province, China to explore new potential As hyperaccumulators. In addition, young plants of 11 Pteris taxa were grown in glasshouse conditions for 12 weeks on As-amended soils with 0, 50 and 200 mg As kg(-1). Results of the field survey showed that the fern Pteris fauriei accumulated over 1000 mg As kg(-1) in its fronds. Of the 11 Pteris taxa, Pteris aspericaulis, Pteris cretica var. nervosa, P. fauriei, Pteris multifida, P. multifida f. serrulata, and Pteris oshimensis were all found to hyperaccumulate As in addition to P. cretica 'Albo-Lineata' and Pteris vittata (already reported as As hyperaccumulators). However, Pteris ensiformis, Pteris semipinnata and Pteris setuloso-costulata showed no evidence of As hyperaccumulation. Results also revealed a constitutive property of As hyperaccumulation in different populations of P. cretica var. nervosa, P. multifida, P. oshimensis and P. vittata.

Growth and lead accumulation by the grasses Vetiveria zizanioides and Thysanolaena maxima in lead-contaminated soil amended with pig manure and fertilizer: a glasshouse study.

Bo Ngam lead mine soils contain high concentrations of lead (up 1% total Pb) and low amounts of organic matter and major nutrients (N, P, K). A glasshouse study was conducted to compare growth performance, metal tolerance and metal uptake by two grasses, Thysanolaena maxima (Roxb.) O. Kuntze and four ecotypes of Vetiveria zizanioides (L.) Nash, syn. Chrysopogon zizanioides (L.) Roberty (three from Thailand: Surat Thani, Songkhla and Kamphaeng Phet, and one from Sri Lanka) and to study the effects of pig manure (20% and 40% w/w) and inorganic fertilizer (75 and 150 mg kg(-1)) amendments to this lead mine soil. The results showed that both T. maxima and V. zizanioides (Surat Thani and Songkhla) could tolerate high Pb concentrations in soil (10750 mg kg(-1)) and had very good growth performance. Application of pig manure increased electrical conductivity (EC) and reduced DTPA-extractable Pb concentration in the soils. Pig manure application improved the growth of vetiver, especially at 20%, application dosage. Vetiver had the highest biomass. T. maxima could not tolerate high EC values. The uptake by roots and transport of Pb to shoots of both species was reduced when soils were amended with pig manure. Application of inorganic fertilizer did not improve growth of vetiver but did improve that of T. maxima. Fertilizer application did not have any great influence on the Pb uptake in vetiver while T. maxima took up more Pb as a result of the fertilizer enhancing its biomass yield. Both species transported low Pb concentrations to shoots (8.3-179 mg kg(-1)) and accumulated higher concentrations in roots (107-911 mg kg(-1)). In summary, both species may be species well suited for phytostabilization in tropical lead mine areas.

On the redshift distribution and physical properties of ACT-selected DSFGs.

We present multi-wavelength detections of nine candidate gravitationally-lensed dusty star-forming galaxies (DSFGs) selected at 218GHz (1.4mm) from the ACT equatorial survey. Among the brightest ACT sources, these represent the subset of the total ACT sample lying in Herschel SPIRE fields, and all nine of the 218GHz detections were found to have bright Herschel counterparts. By fitting their spectral energy distributions (SEDs) with a modified blackbody model with power-law temperature distribution, we find the sample has a median redshift of z = 4.1 - 1.0 + 1.1 (68 per cent confidence interval), as expected for 218GHz selection, and an apparent total infrared luminosity of log 10 ( µ L IR / L ⊙ ) = 13.86 - 0.30 + 0.33 , which suggests that they are either strongly lensed sources or unresolved collections of unlensed DSFGs. The effective apparent diameter of the sample is µ d = 4.2 - 1.0 + 1.7 kpc , further evidence of strong lensing or multiplicity, since the typical diameter of dusty star-forming galaxies is 1.0-2.5 kpc. We emphasize that the effective apparent diameter derives from SED modelling without the assumption of optically thin dust (as opposed to image morphology). We find that the sources have substantial optical depth. ( τ = 4.2 - 1.9 + 3.7 ) to dust around the peak in the modified blackbody spectrum (λ obs ⩽ 500µm), a result that is robust to model choice.

Uptake and accumulation of lead by plants from the Bo Ngam lead mine area in Thailand.

A field survey of terrestrial plants growing on Bo Ngam lead mine area, Thailand, was conducted to identify species accumulating exceptionally high concentrations of lead. Plant and soil samples were collected from five areas. Lead concentrations in surface soil ranged from 325 to 142,400 mg/kg. The highest lead concentration in soil was found at the ore dressing plant area and lowest at a natural pond area. In different areas, the concentrations of lead in plants were different when comparing various study sites. A total of 48 plant species belonging to 14 families were collected from five sampling sites. Twenty-six plant species had lead concentrations more than 1000 mg/kg in their shoots. Three species (Microstegium ciliatum, Polygala umbonata, Spermacoce mauritiana) showed extremely high lead concentrations in their shoots (12,200-28,370 mg/kg) and roots (14,580-128,830 mg/kg).

Phytoextraction of metals from a multiply contaminated soil by Indian mustard.

The effects of nitrilotriacetate (NTA) and citric acid applications on metal extractability from a multiply metal-contaminated soil, as well as on their uptake and accumulation by Indian mustard (Brassica juncea) were investigated. Desorption of metals from the soil increased with chelate concentration, NTA being more effective than citric acid in solubilising the metals. Plants were grown in a sandy soil collected from a contaminated field site and polluted by Cd, Cr, Cu, Pb and Zn. After 43 days of plant growth, pots were amended with NTA or citric acid at 5 mmol kg-1 soil. Control pots were not treated with any chelate. Harvest of plants was performed 1 week after chelate addition. Soil water-, NH4NO3- and DTPA-extractable Cd, Cu, Pb and Zn fractions were enhanced only in the presence of NTA. In comparison to unamended plants, Indian mustard shoot dry weights suffered significant reductions following NTA application. NTA treatment increased shoot metal concentrations by a factor of 2-3, whereas citric acid did not induce any difference compared to the control. Chromium was detected in the above-ground tissues only after NTA amendment. Due to differences in dry matter yield, a significant enhancement of metal uptake was observed in NTA-treated plants for Cu and Zn.

Phytoremediation of soil metals.

The phytoremediation of metal-contaminated soils offers a low-cost method for soil remediation and some extracted metals may be recycled for value. Both the phytoextraction of metals and the phytovolatilization of Se or Hg by plants offer great promise for commercial development. Natural metal hyperaccumulator phenotype is much more important than high-yield ability when using plants to remove metals from contaminated soils. The hypertolerance of metals is the key plant characteristic required for hyperaccumulation; vacuolar compartmentalization appears to be the source of hypertolerance of natural hyperaccumulator plants. Alternatively, soil Pb and Cr6+ may be inactivated in the soil by plants and soil amendments (phytostabilization). Little molecular understanding of plant activities critical to phytoremediation has been achieved, but recent progress in characterizing Fe, Cd and Zn uptake by Arabidopsis and yeast mutants indicates strategies for developing transgenic improved phytoremediation cultivars for commercial use.

Loss of response to beta-adrenoceptor agonists during the maturation of human monocytes to macrophages in vitro.

We have previously reported that human airway macrophages do not respond to the beta-adrenoceptor agonist isoprenaline. The airway macrophage is known to be derived from the blood monocyte. In this study we have assessed the effect of beta-adrenoceptor stimulation on human monocytes matured into macrophages in vitro, to determine whether the lack of response previously observed in the airway macrophage may be a consequence of differentiation. The release of thromboxane B2 (TXB2) from freshly isolated monocytes stimulated by opsonized zymosan (OPZ) was inhibited by 39.3 +/- 5.5% in the presence of isoprenaline (10(-7) M). However, the response was lost in the monocyte-derived macrophage (MDM), where isoprenaline (10(-7) M) caused only 4.0 +/- 9.3% inhibition of OPZ-stimulated TXB2 release. In contrast forskolin (10(-5) M) inhibited MDM TXB2 release by 36.4 +/- 17.3%, indicating that the adenylyl cyclase was functional. Measurement of adenylyl cyclase activity showed that there was a reduction in the basal level, 17.03 +/- 4.1 to 7.9 +/- 4.6 cyclic AMP pmol/min/mg protein, and NaF (10(-2) M)-induced activity, 116.3 +/- 32.1 to 21.9 +/- 12.6 cyclic AMP pmol/min/mg protein, between freshly isolated monocytes and MDMs, respectively. In addition, there was no change in MDM basal adenylyl cyclase activity on exposure to isoprenaline. Thus we have demonstrated the loss of beta-adrenoceptor function during the maturation of human monocytes to macrophages in vitro, despite a functional adenylyl cyclase system. In this respect the monocyte-derived macrophage is like the airway macrophage.

Isoprenaline inhibits thromboxane B2 release from U937 cells.

The U937 monocytic cell line and its differentiated macrophage-like form have been well characterized, illustrating many similarities with their analogous in vivo cells. We examined the release of thromboxane B2 (TXB2) from undifferentiated and differentiated cells after stimulation with opsonized zymosan and investigated whether the release of this mediator could be modified by isoprenaline. After stimulation, the U937 cells released TXB2 in a dose-dependent manner, with the release greater from the differentiated cells. The TXB2 released was inhibited by flurbiprofen (> 10(-8) M; P < .01) and isoprenaline (> 10(-6) M; P < .01), and the inhibition was reversed by propranolol (10(-6) M; P < .02). Thus, it is clear that undifferentiated and differentiated U937 cells release TXB2, which can be inhibited by beta 2-adrenoceptor stimulation. These findings illustrate an important functional difference between the in vivo macrophages and differentiated U937 cells because beta 2-adrenoceptor stimulation does not inhibit mediator release from macrophages.