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PubMed1995

Chloride transport mechanism in swine tracheal submucosal gland cells.

To clarify the mechanism for Cl- transport in swine tracheal submucosal gland cells, we measured chloride (Cl-) flux by means of a Cl(-)-sensitive fluorophore, 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ). An abrupt change of Cl(-)-free bath to a Cl(-)-containing (114 mM) solution induced the Cl- influx into the cells at a rate of 0.52 mM/s (p < 0.05). Removal of sodium (Na+) and the addition of 0.5 mM furosemide significantly reduced the rate of gradient-induced Cl- influx to 0.21 (p < 0.05) and 0.19 mM/s (p < 0.05), respectively. In gland tissue treated with 0.1 mM ouabain, the removal of external potassium (K+) in the presence of 5 mM barium significantly reduced the rate of Cl- influx to 0.21 mM/s (p < 0.05). An abrupt change from a Cl(-)-containing bath to a Cl(-)-free solution induced the Cl- efflux from the cells at a rate of 0.10 mM/s (p < 0.05). Acetylcholine increased the rate of gradient-induced Cl- efflux in a dose-dependent manner to 0.78 mM/s at 10(-6) M. This effect of acetylcholine was significantly diminished by diphenylamine-2-carboxylic acid (DPC, 10(-9) M), a Cl- channel blocker (p < 0.05). Isoproterenol (10(-5) M) had no effect on the Cl- efflux. These findings indicate that a Na-K-Cl co-transporter plays a major role in Cl- entry, and that Cl- efflux was activated by cholinergic receptor stimulation, but not by beta-adrenergic stimulation, via a DPC-inhibitable Cl- channel.

Acetylcholine↗
PubMed1989

Effects of combined receptor antagonists of leukotriene D4 (LTD4) and platelet-activating factor (PAF) on rhesus airway responses to LTD4, PAF and antigen.

Rhesus monkeys with IgE-mediated asthmatic-type responses to Ascaris suum antigen were pretreated with a combination of 2 receptor antagonists to leukotriene D4 (LTD4) and platelet-activating factor (PAF). This combination of anti-LTD4 and anti-PAF was shown to inhibit airway responses to either LTD4 or PAF in separate experiments in these Ascaris airway-reactive animals. When the same combination of LTD4 and PAF receptor antagonists was used to pretreat the same animal prior to aerosol challenge with Ascaris antigen we could not demonstrate inhibition of the antigen-induced airway response. Thus, combined receptor blockade for LTD4 and PAF did not alter IgE-mediated acute airway responses to antigen in this species. We review the current status of rhesus asthma and LTD4 and PAF receptor antagonist activity in this model.

Animals↗
PubMed1992

Comparative studies of furosemide effects on membrane potential and intracellular chloride activity in human and rabbit ciliary epithelium.

Furosemide (1 mM), a potent loop diuretic, caused a 10-mV (n = 14) depolarization of the intracellular potential difference (PDI) of isolated rabbit ciliary epithelium (CE), but produced a 9-mV (n = 5) hyperpolarization of PDI of isolated human CE. In rabbit CE, furosemide consistently depolarized PDI by 13, 7 and 8 mV in HCO3(-)-free Ringer, Na(+)-free Ringer and after BaCl2 treatment, respectively. The depolarization of PDI was reduced to 2 mV (n = 11) in Cl(-)-free conditions. A hyperpolarization of PDI caused by furosemide that was quantitatively similar to that seen in normal Ringer also occurred in human CE during immersion in HCO3(-)-free Ringer, Na(+)-free Ringer and after BaCl2 treatment. There was a small hyperpolarization (3 mV) of PDI in Cl(-)-free conditions. Human or rabbit tissue-cultured nonpigmented ciliary epithelial cells were loaded with the Cl(-)-sensitive fluorophore 6-methoxy-N-(3-sulfopropyl) quinolinium (SPQ) in hypotonic solution (145 mosm) for 4 min at 37 degrees C. Furosemide decreased intracellular Cl- fluorescence activity of both human and rabbit ciliary epithelial cells by 30 +/- 5 (n = 8) and 25 +/- 7% (n = 13), respectively, when the cells were immersed in Cl(-)-rich solution. It is suggested that a furosemide-sensitive Cl- movement exists in both rabbit and human CE, although the mode of Cl- movement to the aqueous across CE may differ between these species.

Animals↗
PubMed1990

Effect of platelet-activating factor receptor antagonism on endotoxin-induced lung dysfunction in awake sheep.

To test the hypothesis that PAF partially mediates endotoxin-induced lung dysfunction, we studied the effects of two structurally dissimilar PAF receptor antagonists (SRI 63-441 and WEB 2086) on endotoxin-induced lung dysfunction in chronically instrumented awake sheep. Each animal was studied three times in varied order: infusion of endotoxin alone (Escherichia coli endotoxin 0.5 micrograms/kg over 20 min [E]), infusion of the competitive platelet-activating factor (PAF) receptor antagonist alone, or with endotoxin given 1 h after beginning the 6-h drug infusion (E + SRI, E + WEB). Neither drug alone had significant effects on any of the measured variables, but both were able to abolish the pulmonary pressor effect of a 0.25-micrograms/kg bolus of PAF. SRI 63-441 (10 to 20 mg/kg/h) attenuated the endotoxin-induced pulmonary hypertension (peak pulmonary arterial pressure, 53 +/- 12 versus 65 +/- 7 cm H2O; p greater than 0.05) and fall in dynamic compliance of the lungs (to 65.1 +/- 9.8% baseline versus 32.6 +/- 5.1% baseline). Lung lymph flow increased 6.1- and 5.8-fold at 2 and 5 h for (E) versus 1.9- and 2.5-fold at identical time points for (E + SRI). SRI 63-441 attenuated the acute leukopenia noted after endotoxemia. WEB 2086 (20 mg/kg/h) similarly attenuated the late alterations in lung mechanics and lymph flow caused by endotoxin, but it had little effect on the early pulmonary hypertension and lung mechanic changes. Both agents significantly attenuated the rise in lymph thromboxane B2 levels after endotoxemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Novel cell imaging techniques show induction of apoptosis and proliferation in mesothelial cells by asbestos.

We developed in situ dual-fluorescence detection techniques for measuring apoptosis and proliferation simultaneously in single dishes of cells. The deoxyribonucleic acid (DNA)-specific labeling method, terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate nick-end labeling (TUNEL), first was used in conjunction with a 4',6-diamidino-2-phenylindole (DAPI) counterstain to detect and measure morphologic characteristics of apoptotic rat pleural mesothelial (RPM) cells isolated from Fischer 344 rats and exposed to 300 microM hydrogen peroxide (H2O2). For this purpose, 100 TUNEL-positive nuclei were measured while being viewed with DAPI counterstaining for area, perimeter, longest diameter, and average diameter, using imaging software and an image-collection apparatus. We then exposed cells to a range of concentrations of crocidolite asbestos and putative apoptotic and mitogenic agents. Exposure to crocidolite asbestos (5 microg/cm2) caused a striking dose-dependent apoptotic response at 24 h, 48 h, and 72 h. The nonfibrous crocidolite analogue riebeckite failed to induce apoptosis. At 24 h, tumor necrosis factor-alpha (TNF-alpha) (10 ng/ml) caused an increase in apoptotic nuclei. A second method, utilizing an antibody to 5'-bromodeoxyridine (BrdU) and oxazole yellow homodimer (YOYO), showed a dose-dependent increase in proliferation occurring in cells exposed to asbestos (5 microg/cm2) at 48 h and 72 h. In addition, increased numbers of rat pleural mesothelial (RPM) cells exposed to 12-O-tetradecanoylphorbol-13-acetate (TPA), TNF-alpha, and epidermal growth factor (EGF) exhibited incorporation of BrdU at these time points, although total numbers of cells per unit area were unchanged. Results indicate a dynamic balance between apoptosis and increased DNA synthesis after exposure of mesothelial cells to asbestos.

Animals↗
PubMed2004

Enhancement of P2X(7)-induced pore formation and apoptosis: an early effect of diabetes on the retinal microvasculature.

PURPOSE: A sight-threatening complication of diabetes is cell death in retinal capillaries. Currently, the mechanisms responsible for this classic manifestation of diabetic retinopathy remain uncertain. The hypothesis for the current study is that diabetes increases the vulnerability of retinal microvessels to the potentially lethal consequences of having their P2X(7) purinoceptors activated. A pathophysiological role is suspected for these receptor-operated channels because, in addition to transducing retinovascular responses to extracellular adenosine triphosphate (ATP), the sustained opening of these channels can induce the formation of large transmembrane pores. METHODS: In pericyte-containing retinal microvessels that were freshly isolated from nondiabetic and streptozotocin-injected rats, cells with pores were identified by the uptake of YO-PRO-1. Cell viability was assayed by trypan blue dye exclusion, and cleaved caspase-3 immunoreactivity, TUNEL positivity, and nuclear morphology were used to detect apoptotic cells. Patch-clamp recordings assessed electrophysiological parameters. RESULTS: Activation of P2X(7) receptors caused large pores to form and apoptosis to occur in retinal capillaries of nondiabetic and diabetic rats. Of importance to diabetes, the agonist concentration needed to open pores and trigger apoptosis decreased markedly soon after the onset of streptozotocin-induced hyperglycemia. However, despite this increased sensitivity, diabetes minimally affected the P2X(7)-induced ionic currents. Thus, rather than upregulate the number of functional P2X(7) receptor/channels, diabetes appears to facilitate the channel-to-pore transition that occurs during activation of these purinoceptors. In this way, normally nonlethal concentrations of P2X(7) ligands may trigger apoptosis in microvessels of the diabetic retina. CONCLUSIONS: A diabetes-induced increase in the vulnerability of retinal microvessels to the lethal effect of P2X(7) receptor activation may be a previously unrecognized mechanism by which diabetic retinopathy progresses.

Adenosine Triphosphate↗
PubMed2006

NAD+-induced vasotoxicity in the pericyte-containing microvasculature of the rat retina: effect of diabetes.

PURPOSE: It was recently proposed that activation of P2X(7) purinoceptors may play a role in causing cell death in the pericyte-containing microvasculature of the diabetic retina. This hypothesis is supported by the observation that diabetes enhances lethal pore formation in retinal microvessels exposed to synthetic P2X(7) agonists. The goal of this study was to determine whether purinergic vasotoxicity can be triggered by the endogenous molecule nicotinamide adenosine dinucleotide (NAD(+)), which is a substrate for ecto-ribosylation reactions known to activate P2X(7) receptor/channels in other cell types. METHODS: Pericyte-containing retinal microvessels were isolated from normal and streptozotocin-injected rats. Trypan blue dye exclusion was used to assess cell viability, YO-PRO-1 uptake was used to identify cells with P2X(7)-induced pores, and ethenoadenosine antibodies were used to detect ecto-adenosine diphosphate (ADP)-ribosyltransferase (ART) activity. RESULTS: In freshly isolated retinal microvessels, it was found that extracellular NAD(+), but not its catabolites, caused cell death (half-maximal effective concentration [EC(50)] = 2 nM) by a mechanism involving the activation of P2X(7) purinoceptors and the formation of transmembrane pores. A series of experiments provided evidence that NAD(+), which is not a direct purinergic agonist, serves as a substrate for ecto-ribosylation reactions that subsequently trigger P2X(7)-dependent cell death in the retinal microvasculature. Soon after the onset of diabetes, the sensitivity of retinal microvessels to the vasotoxic effect of extracellular NAD(+) increased by approximately 100-fold. CONCLUSIONS: Purinergic vasotoxicity triggered by extracellular NAD(+) is a newly recognized mechanism that may contribute to the cell death observed in the pericyte-containing microvascular of the diabetic retina.

ADP Ribose Transferases↗
PubMed1987

Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats.

Within 20 min after intraperitoneal injection of Salmonella enteritidis endotoxin in rats, blood platelet-activating factor (PAF) increased from 4.3 +/- 1.3 to 13.7 +/- 2.0 ng/ml (P less than 0.01) and lung PAF from 32.3 +/- 4.9 to 312.3 +/- 19.6 ng (P less than 0.01), but not lung lavage PAF. We tested the effect of PAF receptor antagonists, CV 3988 and SRI 63-441, on endotoxin-induced hemodynamic changes and lung vascular injury. Pretreatment with CV 3988 attenuated systemic hypotension, preserved hypoxic pulmonary vasoconstriction, and prolonged survival of awake catheter-implanted endotoxin-treated (20 mg/kg) rats. Pretreatment with SRI 63-441 prevented the depressed hypoxic pulmonary vasoconstriction after low dose (2 mg/kg) endotoxin. Both CV 3988 and SRI 63-441 blocked the increased extravascular accumulation of 125I-albumin and water in perfused lungs isolated from endotoxin-treated rats. We conclude that PAF is produced in the lung during endotoxemia and may be an important mediator of the systemic and pulmonary hemodynamic changes as well as the acute lung vascular injury after endotoxemia.

Animals↗
PubMed1989

Inhibition of endotoxin-induced bacterial translocation in mice.

The primary functions of the gut are to absorb nutrients and exclude bacteria and their products. However, under certain circumstances the gut may lose its barrier function and serve as a reservoir for systemic microbial infections. These experiments were performed to determine the mechanisms whereby endotoxin causes bacteria to escape (translocate) from the gut. Bacteria translocated from the gut to the mesenteric lymph nodes of mice challenged with nonlethal doses of Escherichia coli 026:B6 or E. coli 0111:B4 endotoxin. Physical disruption of the gut mucosal barrier appears to be the primary mechanism whereby endotoxin promotes bacterial translocation. Mucosal injury and endotoxin-induced bacterial translocation were reduced by inhibition (allopurinol) or inactivation (tung-sten diet) of xanthine oxidase activity (P less than 0.01), but were not affected by the platelet-activation factor antagonists, SRI 63-441 or BN 52021. Because the inhibition or inactivation of xanthine oxidase activity reduced both the extent of mucosal injury and endotoxin-induced bacterial translocation, the effect of endotoxin on the gut appears to be mediated, at least to some degree, by xanthine oxidase-generated, oxygen-free radicals.

Allopurinol↗
PubMed1996

Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death.

In the present study, it was shown that physiologically relevant levels of the proinflammatory cytokine TNFalpha induced apoptosis in rat cardiomyocytes in vitro, as quantified by single cell microgel electrophoresis of nuclei ("cardiac comets") as well as by morphological and biochemical criteria. It was also shown that TNFalpha stimulated production of the endogenous second messenger, sphingosine, suggesting sphingolipid involvement in TNFalpha-mediated cardiomyocyte apoptosis. Consistent with this hypothesis, sphingosine strongly induced cardiomyocyte apoptosis. The ability of the appropriate stimulus to drive cardiomyocytes into apoptosis indicated that these cells were primed for apoptosis and were susceptible to clinically relevant apoptotic triggers, such as TNFalpha. These findings suggest that the elevated TNFalpha levels seen in a variety of clinical conditions, including sepsis and ischemic myocardial disorders, may contribute to TNFalpha-induced cardiac cell death. Cardiomyocyte apoptosis is also discussed in terms of its potential beneficial role in limiting the area of cardiac cell involvement as a consequence of myocardial infarction, viral infection, and primary cardiac tumors.

Analysis of Variance↗
PubMed2001

Texture analysis of fluorescence lifetime images of AT- and GC-rich regions in nuclei.

We used intensity and fluorescence lifetime microscopy (FLIM) of 3T3 nuclei to investigate the existence of AT-rich and GC-rich regions of the nuclear DNA. Hoechst 33258 (Ho) and 7-aminoactinomycin D (7-AAD) were used as fluorescence probes specific for AT and GC base pairs, respectively. YOYO-1 (Yo) was used as a dye that displays distinct fluorescence lifetimes when bound to AT or GC base pairs. We combined fluorescence imaging of Ho and 7-AAD with time-resolved measurements of Yo and took advantage of an additional information content of the time-resolved fluorescence. Because a single nucleus could not be stained and measured with all three dyes, we used texture analysis to compare the spatial distribution of AT-rich and GC-rich DNA in 100 nuclei in different phases of the cell cycle. The fluorescence intensity-based analysis of Ho- or 7-AAD-stained images indicates increased number and larger size of the DNA condensation centers in the G2/M-phases compared to G0/1-phases. The lifetime-based study of Yo-stained images suggests spatial separation of the AT- or GC-rich DNA regions in the G2/M-phase. Texture analysis of fluorescence intensity and lifetime images was used to quantitatively study the spatial change of condensation and separation of AT- and GC-rich DNA during the cell cycle.

3T3 Cells↗
PubMed1997

DNA staining for fluorescence and laser confocal microscopy.

We examined five nucleic acid binding fluorescent dyes, propidium iodide, SYBR Green I, YO-PRO-1, TOTO-3, and TO-PRO-3, for nuclear DNA staining, visualized by fluorescence and laser confocal microscopy. The optimal concentration, co-staining of RNA, and bleaching speeds were examined. SYBR Green I and TO-PRO-3 almost preferentially stained the nuclear DNA, and the other dyes co-stained the cytoplasmic RNA. RNAse treatment completely prevented the cytoplasmic RNA staining. In conventional fluorescence microscopy, these dyes can be used in combination with fluorescence-labeled antibodies. Among the dyes tested, TOTO-3 and TO-PRO-3 stained the DNAs with far-red fluorescence under red excitation. Under Kr/Ar-laser illumination, TOTO-3 and TO-PRO-3 were best suited as the nuclear staining dyes in the specimens immunolabeled with fluorescein and rhodamine (or Texas red).

Animals↗
PubMed2006

Nanoelectropulse-driven membrane perturbation and small molecule permeabilization.

BACKGROUND: Nanosecond, megavolt-per-meter pulsed electric fields scramble membrane phospholipids, release intracellular calcium, and induce apoptosis. Flow cytometric and fluorescence microscopy evidence has associated phospholipid rearrangement directly with nanoelectropulse exposure and supports the hypothesis that the potential that develops across the lipid bilayer during an electric pulse drives phosphatidylserine (PS) externalization. RESULTS: In this work we extend observations of cells exposed to electric pulses with 30 ns and 7 ns durations to still narrower pulse widths, and we find that even 3 ns pulses are sufficient to produce responses similar to those reported previously. We show here that in contrast to unipolar pulses, which perturb membrane phospholipid order, tracked with FM1-43 fluorescence, only at the anode side of the cell, bipolar pulses redistribute phospholipids at both the anode and cathode poles, consistent with migration of the anionic PS head group in the transmembrane field. In addition, we demonstrate that, as predicted by the membrane charging hypothesis, a train of shorter pulses requires higher fields to produce phospholipid scrambling comparable to that produced by a time-equivalent train of longer pulses (for a given applied field, 30, 4 ns pulses produce a weaker response than 4, 30 ns pulses). Finally, we show that influx of YO-PRO-1, a fluorescent dye used to detect early apoptosis and activation of the purinergic P2X7 receptor channels, is observed after exposure of Jurkat T lymphoblasts to sufficiently large numbers of pulses, suggesting that membrane poration occurs even with nanosecond pulses when the electric field is high enough. Propidium iodide entry, a traditional indicator of electroporation, occurs with even higher pulse counts. CONCLUSION: Megavolt-per-meter electric pulses as short as 3 ns alter the structure of the plasma membrane and permeabilize the cell to small molecules. The dose responses of cells to unipolar and bipolar pulses ranging from 3 ns to 30 ns duration support the hypothesis that a field-driven charging of the membrane dielectric causes the formation of pores on a nanosecond time scale, and that the anionic phospholipid PS migrates electrophoretically along the wall of these pores to the external face of the membrane.

Benzoxazoles↗
PubMed2005

An efficient intrathecal delivery of small interfering RNA to the spinal cord and peripheral neurons.

We have developed a highly effective method for in vivo gene silencing in the spinal cord and dorsal root ganglia (DRG) by a cationic lipid facilitated delivery of synthetic, small interfering RNA (siRNA). A siRNA to the delta opioid receptor (DOR), or a mismatch RNA, was mixed with the transfection reagent, i-Fect (vehicle), and delivered as repeated daily bolus doses (0.5 microg to 4 microg) via implanted intrathecal catheter to the lumbar spinal cord of rats. Twenty-four hours after the last injection, rats were tested for antinociception by the DOR selective agonist, [D-Ala(2), Glu(4)]deltorphin II (DELT), or the mu opioid receptor (MOR) selective agonist, [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO). Pretreatment with the siRNA, but not the mismatch RNA or vehicle alone, blocked DELT antinociception dose-dependently. The latter was concomitant with a reduction in the spinal immunoreactivity and receptor density of DOR, and in DOR transcripts in the lumbar DRG and spinal dorsal horn. Neither siRNA nor mismatch RNA pretreatment altered spinal immunoreactivity of MOR or antinociception by spinal DAMGO, and had no effect on the baseline thermal nociceptive threshold. The inhibition of function and expression of DOR by siRNA was reversed by 72 hr after the last RNA injection. The uptake of fluorescence-tagged siRNA was detected in both DRG and spinal cord. The low effective dose of siRNA/i-Fect complex reflects an efficient delivery of the siRNA to peripheral and spinal neurons, produced no behavioral signs of toxicity. This delivery method may be optimized for other gene targets.

Animals↗
PubMed2005

Lipoprotein aggregation protects human monocyte-derived macrophages from OxLDL-induced cytotoxicity.

Oxidative modifications render low density lipoprotein cytotoxic and enhance its propensity to aggregate and fuse into particles similar to those found in atherosclerotic lesions. We showed previously that aggregation of oxidized LDL (OxLDL) promotes the transformation of human macrophages into lipid-laden foam cells (Asmis, R., and J. Jelk. 2000. Large variations in human foam cell formation in individuals. A fully autologous in vitro assay based on the quantitative analysis of cellular neutral lipids. Atherosclerosis. 148: 243-253). Here, we tested the hypothesis that aggregation of OxLDL enhances its clearance by human macrophages and thus may protect macrophages from OxLDL-induced cytotoxicity. We found that increased aggregation of OxLDL correlated with decreased macrophage injury. Using 3H-labeled and Alexa546-labeled OxLDL, we found that aggregation enhanced OxLDL uptake and increased cholesteryl ester accumulation but did not alter free cholesterol levels in macrophages. Acetylated LDL was a potent competitor of aggregated oxidized LDL (AggOxLDL) uptake, suggesting that scavenger receptor A plays an important role in the clearance of AggOxLDL. Inhibitors of actin polymerization, cytochalasin B, cytochalasin D, and latrunculin A, also prevented AggOxLDL uptake and restored OxLDL-induced cytotoxicity. This suggests that OxLDL-induced macrophage injury does not require OxLDL uptake and may occur on the cell surface. Our data demonstrate that aggregation of cytotoxic OxLDL enhances its clearance by macrophages without damage to the cells, thus allowing macrophages to avoid OxLDL-induced cell injury.

Actins↗
PubMed1991

Sustained effects of platelet-activating factor infusion in piglets.

Acute exposure to platelet-activating factor (PAF) causes severe pulmonary vasoconstriction (PV), but its action may be markedly limited by tachyphylaxis. To determine the effects of PAF exposure per se and the effects compared with the hypoxemic state (33 +/- 1 mm Hg), PAF infusions (0.05-0.15 nmol/kg/min x 30-180 min) were administered to 15 open-chested, anesthetized, neonatal piglets before and during administration of selective receptor blockers to PAF (SRI 63,441, 5 mg/kg i.v. or WEB 2086, 10 mg/kg i.v.) or vehicle. Measurements included mean pulmonary (PAP) and systemic arterial pressures, cardiac index, right and left ventricular pressures and dimensions, and coronary blood flow. Mean PAP and pulmonary vascular resistance index rose in response to 30 min PAF infusion (14 +/- 1 to 30 +/- 1 mm Hg and 4500 +/- 700 to 16,400 +/- 1900 dynes s cm-5.kg, both p less than 0.01, n = 10). Similar changes occurred when PAF was infused for 180 min (n = 5). Other parameters were unaffected. Acute hypoxia also increased in PAP and pulmonary vascular resistance index (17 +/- 1 to 32 +/- 2 mm Hg and 6400 +/- 900 to 17,100 +/- 1800 dynes s cm-5.kg, both p less than 0.01) and did not alter other measured variables. Treatment with SRI 63,441 prevented PAF-induced increases in PAP (14 +/- 1 to 14 +/- 1 mm Hg, p less than 0.05) and pulmonary vascular resistance index (5300 +/- 900 to 5500 +/- 800 dynes s cm-5.kg, p less than 0.05) but failed to alter the response to hypoxia. SRI 63,441 and WEB 2086, administered during PAF infusion, rapidly reversed PAF action. Vehicle had no effect. We conclude that PAF can produce severe and sustained PV in vivo and that PAF receptor blockade may be useful in treatment of neonatal disease featuring PAF-mediated PV. PAF receptors may not be involved in PV induced by hypoxia.

Animals↗
PubMed2002

Normal function of the cystic fibrosis conductance regulator protein can be associated with homozygous (Delta)F508 mutation.

Cystic fibrosis (CF) is caused by mutations of the gene encoding for the CFTR (CF transmembrane conductance regulator) protein. The most frequent mutation, the (Delta)F508 mutation, results in a defective cAMP-regulated chloride transport in the epithelial cells. The spectrum of clinical manifestations in patients bearing homozygous (Delta)F508 mutations can vary considerably, suggesting that, in the patients with a mild disease, CFTR could be partly functional. To test this hypothesis, we explored in nasal ciliated epithelial cells (NCC) of 9 control subjects and 23 (Delta)F508 homozygous patients the anion conductive pathway by a halide sensitive fluorescent dye assay SPQ (6-methoxy-N-3'-sulfopropylquinolinium) and the CFTR transcript levels by RT-PCR. As 50% represented the lowest fraction of the control subjects NCC demonstrating a cAMP-dependent conductance, a CF patient was considered as "cAMP responder" if at least 50% of the NCC tested displayed a cAMP-dependent conductive pathway. According to these criteria, 8 of the 23 patients were considered as cAMP responders. They had a significantly less severe disease considering the respiratory function and infectious status. The amount of CFTR mRNA did not differ between the control subjects and the patients. No statistical correlation could be found between the transcript level and the expression of a cAMP conductive pathway. This cAMP-dependent Cl(-) conductance detected in homozygous NCC could be due to a residual CFTR activity and may explain the mild phenotypes observed in some (Delta)F508 homozygous patients.

Chlorides↗