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PubMed1992

An interspecies comparison of the phagocytosis and dissolution of 241AmO2 particles by rat, dog and monkey alveolar macrophages in vitro.

Because of the role that alveolar macrophages (PAM) play in the pulmonary clearance of inhaled particles via mechanical transport and dissolution, understanding the uptake and dissolution of particles by these cells might provide insight into the mechanisms of particle dissolution in lungs of various species and hence facilitate the extrapolation of animal data to humans. Therefore, experiments were conducted to study the phagocytosis and dissolution of 241AmO2 particles by rat, dog and monkey PAM in vitro. Rat, dog and monkey PAM were exposed for up to 72 h to 0.19, 0.93 or 4.6 kBq/ml 241Am, after which cell viability was determined. The 241Am concentration, 4.63 kBq/ml, was used for the phagocytosis and dissolution experiments. The phagocytosis and dissolution of 241AmO2 particles were followed up to 20 and 72 h, respectively. Dog and monkey PAM took up 241AmO2 particles at similar rates, whereas rat PAM phagocytosed only 60% of the amount phagocytosed by dog and monkey PAM at 20 h. The PAM of the three species dissolved 241AmO2 particles at similar rates; 8-10% was dissolved by 72 h. The results of the 241AmO2 uptake in vitro may reflect in vivo situations, where the differences in uptake seen in vitro would probably diminish at later times after exposure. The dissolution results imply that the dissolution of 241AmO2 particles by alveolar macrophages of the three species might be species-independent. This, at least, might be true for dog and monkey, where in vivo data have shown that 241AmO2 was translocated similarly in both species. Finally, the alveolar macrophage culture system provides a useful simulation to investigate uptake and dissolution of inhaled particles.

Americium↗

PubMed1979

Origin, Kinetics, and characteristics of pulmonary macrophages in the normal steady state.

Pulmonary macrophages of mice in the steady state were isolated by lavage with PBS containing EDTA and subsequent enzymatic digestion of tissue with pronase and DNA-ase. By this method, the total pulmonary macrophage population was obtained in two cell suspensions, one with a pure population of pulmonary alveolar macrophages (PAM) and the other with a mixed population of pulmonary alveolar and pulmonary tissue macrophages (PTM). The morphological, cytochemical, and functional characteristics of both PAM and PTM were like those of mature tissue macrophages except for the presence of C3 receptors. These receptors were almost absent on PAM and present on a larger number of cells in the mixed population of PAM and PTM. The total pulmonary macrophage population of mice in the steady state is approximately equal to 2 x 10(6), of which about 93% are PAM and about 7% are PTM. In labeling experiments with 3H-thymidine, the low in vitro labeling indices (less than 3%) for both PAM and the mixture of PAM and PTM, showed that both are essentially nondividing cells. In vivo labeling studies showed an increase in the number of labeled macrophages that can only be attributed to labeled monocytes migrating into the lungs. Additional evidence was provided by a decrease in the labeling indices of pulmonary macrophages when mice were treated with hydrocortisone acetate, which causes a severe monocytopenia, thus preventing monocyte influx into the lungs. Confirmation of the bone marrow origin was obtained in mice labeled after x-irradiation with partial bone marrow shielding: labeled pulmonary macrophages were found in the exposed lungs. In all experiments, the labeling indices were identical in the two macrophage populations isolated. These results show that the influx of monocytes is the source of cell renewal for the pulmonary macrophages. No indications for an interstitial division or maturation compartment in the lung were found. Quantitation of the efflux of labeled monocytes from the blood, and the number of labeled pulmonary macrophages, showed that in the steady state about 15% of the monocytes leaving the circulation become pulmonary macrophages and that the turnover time of pulmonary macrophages is approximately equal to 27 d.

Animals↗

PubMed1975

Effects of oxygen exposure on it vitro function of pulmonary alveolar macrophages.

Bacterial infection may complicate pulmonary oxygen (O2) toxicity, and animals exposed to high O2 concentrations show depressed in vivo pulmonary bacterial inactivation. Therefore, in vitro studies were undertaken to define the mechanism by which O2 alters pulmonary antibacterial activity. Normal and BCG pretreated rabbits were exposed to 100% O2 for 24, 48, and 72-h periods. Pulmonary alveolar macrophages (PAM) were obtained from the experimental animals and from nonoxygen exposed controls by bronchopulmonary lavage. O2 exposure did not alter cell yield or morphology. PAMs were suspended in 10% serum-buffer, and phagocytosis of (14C)Staphylococcus aureus 502A and (14C)Pseudomonas aeruginosa was measured. Comparison of the precent uptake of the 14C-labeled S. aureus after a 60-min incubation period demonstrated that normal PAMs exposed to O2 for 48 h showed a statistically significant increase in phagocytosis when compared to their controls (43.5 vs. 29.2%). A similar, but smaller increase was seen after 24-h O2 exposures. 48 and 72-h O2 exposures produced no significant changes in phagocytosis in PAMs from BCG-stimulated rabbits. Normal PAMs also showed an increased phagocytosis of Ps. aeruginosa after 48-h oxygen exposure. No impairment of in vitro bactericidal activity against either S. aureus 502A or Ps. aeruginosa could be demonstrated in PAMs from normal rabbits exposed to O2 for 48 h. These results indicate that the in vitrophagocytic and bactericidal capacity of the rabbit PAM is relatively resistant to the toxic effects of oxygen, and that imparied in vivo activity may possibly be mediated by effects other than irreversible metabolic damage to these cells. The mechanism for the observed stimulation of phagocytosis remains to be determined.

Animals↗

PubMed2026

Structure-Function Analysis of the Benzyloxy Moiety of the Delta-Opioid Receptor Positive Modulator BMS-986187: Identification of a Derivative with High Selectivity for the Delta-Opioid Receptor over the Mu-Opioid Receptor In Vitro and In Vivo.

Positive allosteric modulators (PAMs) of the delta-opioid receptor (DOR) enhance endogenous opioid signaling while avoiding the convulsant liability of orthosteric agonists. However, the prototypical DOR-PAM, BMS-986187, also potentiates mu-opioid receptor (MOR) signaling, raising concerns regarding respiratory depression and abuse liability. Here, we report a structure-activity study of the benzyloxy moiety of BMS-986187 to improve selectivity for DOR over MOR, while retaining DOR-PAM potency. Fifty-two new analogues and 12 previously reported ones featuring mono- and disubstitution of the benzyl ring and phenyl-heterocycle replacements were synthesized and evaluated in β-arrestin2 recruitment assays. Ortho-substituted derivatives consistently enhanced DOR-PAM potency, although often increased MOR-PAM activity. One pyridyl derivative (compound 35) retained high DOR-PAM potency and efficacy (EC50 = 0.1 μM, Emax = 91%) with no detectable MOR activity. In mice, compound 35 enhanced DOR-mediated reversal of nitroglycerin-induced hyperalgesia, an effect absent in DOR-knockout mice, without enhancing MOR-mediated antinociception, demonstrating in vivo selectivity.

Receptors, Opioid, delta↗

PubMed1979

Drug uptake into everted intestinal sacs. I. Enhancement by hypertonicity.

The transfer of the cationic drugs, pralidoxime (PAM) and tetraethylammonium, and anionic ampicillin from the mucosal-to-serosal sides of everted rat jejunal sacs is enhanced by mucosal hypertonicity. PAM uptake, which is proportional to initial mucosal concentrations up to 2.3 mM, is enhanced by mucosal hypertonicity due to addition of sodium, potassium, lithium and choline chloride, sodium sulfate, and the nonionic solutes, urea, sucrose, and mannitol. Bicarbonate, Tris, or phosphate buffer and the presence of magnesium and calcium do not affect this hypertonicity-induced acceleration of PAM passage. Serosal osmolality has no effect on transfer and mucosal hypertonicity is equally effective in the presence and absence of a transmural osmotic gradient. This observation and minimal changes in the concentration of inulin placed in the sacs suggest that fluid shifts and solvent drag are not responsible for the enhanced mucosal-to-serosal transfer of PAM from hypertonic buffer. Mucosal hypertonicity at 450 mosmol/kg causes reversible enhancement of PAM transfer, whereas the effect of 600 mosmol/kg cannot be reversed by replacing the tissue in isotonic buffer. The effect of osmotic manipulation on PAM transfer across the intestine thus differs from its effect on the passage of other ionized species and drugs across other epithelia.

Ampicillin↗

PubMed1979

Induction of ouabain-resistant mutation and sister chromatid exchanges in Chinese hamster cells with chemical carcinogens mediated by human pulmonary macrophages.

Pulmonary macrophages (PAM) metabolically activated benzo[a]pyrene [B(a)P] and its proximate carcinogenic metabolite, (+/-)trans 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (7,8-diol), to ultimate mutagens that were detected in cocultivated Chinese hamster V79 cells. Increases in the frequency of ouabainresistant (O(r)) mutations and sister chromatid exchanges were found in V79 cells only when they were cocultivated with both PAM and the chemical procarcinogens. 7,8-Diol caused higher frequencies of both O(r) mutations and sister chromatid exchanges than did the parent compound, B(a)P. When metabolically activated by PAM the mean O(r) mutation frequency caused by B(a)P was 9 O(r) mutants/10(6) surviving V79 cells per 10(6) PAM and a 10-fold interindividual variation (range, 2-21) was found. The mean O(r) mutation frequency caused by 7,8-diol was 64 and a ninefold interindividual variation (range, 14-120) was found. In the absence of PAM, the O(r) mutation frequency in V79 cells was one or less O(r) mutant per 10(6) survivors. 7,8-Benzoflavone, an inhibitor of mixed function oxidases, reduced the frequencies of O(r) mutations and of sister chromatid exchanges in V79 cells caused by 7,8-diol and B(a)P. As expected 7,8-benzoflavone did not influence the frequency of O(r) mutations caused by one of the ultimate mutagens derived from B(a)P and 7,8-diol, (+/-)7beta, 8alpha-dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. These data are consistant with the hypothesis that PAM may play a role in the activation of environmental chemical procarcinogens.

Adenocarcinoma↗

PubMed1976

[Inhibition of cholinesterase activity induced by pyridaphenthion].

Inhibitory effects on cholinesterase (ChE) activity in blood of the rabbit induced by pyridaphenthion(PD), an organophosphorus compound, and effects of 2-pyridine aldoxime methiodide(PAM) on this inhibition were examined. 1) Experimental results within 24 hr: An oral administration of each dose of PD(100 approximately 750 mg/kg) gradually decreased ChE activity and ChE activity value decreased to 20.5% in the erythrocytes and 21.5% in the plasma 24 hr after administration of 500 mg/kg of PD. However, this value recovered remarkably with an intravenous injection of PAM. The ChE activity value was 55.5% in the erythrocytes and 41.4% in the plasma with a single injection, and respectively 67.8% and 59.1% when PAM was injected three times. 2) Experimental results for 14 days: Following an increase of the administered dose (100 approximately 400 mg/kg) of PD, a decrease in ChE activity was apparent and a recovery to normal values was delayed. This inhibition could be ameliorated quickly with an injection of PAM. Considering that PAM does not have remarkable detoxicative effects on organophosphorus compounds which have a low toxicity, PAM appears to be a promising antidote against PD.

Administration, Oral↗

PubMedDate not supplied

Immunological characterization of pulmonary intravascular macrophages.

Pulmonary intravascular macrophages (PIMs) are lung macrophages found apposed to the endothelium of pulmonary capillaries. In many species, they are responsible for the clearance of blood-borne particulates and pathogens; however, little else is known about their roles as immunologic effector cells. We compared PIMs with pulmonary alveolar macrophages (PAMs) to determine the relative immunological activities of these two cell populations. Our results suggested that both populations possess similar phagocytic and bactericidal activities. In assays measuring cytotoxicity, PIMs were more cytotoxic than PAMs against virally infected target cells; however, differences between these macrophage populations were not as marked when noninfected targets were used. LPS-stimulated PIMs produced more T-cell proliferative cytokines than PAMs, and both populations of nonstimulated macrophages produced similar amounts of the cytokines. In contrast, PAMs produced more TNF alpha and NO2- than PIMs when both populations were stimulated with LPS; however, nonstimulated PAMs and PIMs produced similar amounts of TNF alpha and NO2. These data suggest that bovine PIMs are immunologically active. Differences between the degrees of activity of PIMs and PAMs indicate that these macrophage populations may have different roles in lung surveillance.

Animals↗

PubMed1992

Stimulation and suppression of the oxygenation activity of porcine pulmonary alveolar macrophages by Actinobacillus pleuropneumoniae and its metabolites.

The effects of Actinobacillus (Haemophilus) pleuropneumoniae and its metabolites on the oxygenation activity of porcine pulmonary alveolar macrophages (PAM) were studied, using a chemiluminescence technique. Actinobacillus pleuropneumoniae strains of serotypes 2, 3, and 9 in a dose of 1, 10, and 100 colony-forming units/macrophage first stimulated the oxygen radical production of PAM. After having reached a peak value, oxygenation activity decreased, finally resulting in total suppression of PAM. All these effects were neutralized by homologous convalescent pig sera that had been adsorbed onto inactivated A pleuropneumoniae strains. Moreover, cross-neutralization was shown between serotypes 2 and 3. Inactivated A pleuropneumoniae strains did not influence the oxidative activity of PAM. Undiluted and lower dilutions of sterile A pleuropneumoniae culture supernatants were toxic for PAM, whereas higher dilutions of the supernatants stimulated oxygen radical production of the macrophages. These effects were heat-sensitive and were neutralized by homologous convalescent pig sera. Cross-neutralization was shown between serotypes 2 and 3. These findings indicated that stimulation and inhibition of the oxygenation activity of PAM are attributable to heat-sensitive metabolites produced by A pleuropneumoniae.

Actinobacillus pleuropneumoniae↗

PubMed1979

Hypersensitivity reactions to iv melphalan during treatment of multiple myeloma: Cancer and Leukemia Group B experience.

Ten patients developed allergic reactions to iv melphalan (L-PAM) during therapy for multiple myeloma. The incidence of such reactions was 2.4% among 425 patients receiving iv L-PAM with or without other drugs and 3.9% among 255 patients receiving iv L-PAM alone. Only one such reaction was demonstrated in 294 patients who initially received oral L-PAM. The median day of first reaction to iv L-PAM was Day 222 (range, Days 44-909) and the median total dose prior to a reaction was 185 mg (range, 51-250 mg). Of five patients who subsequently received oral L-PAM, four developed a reaction similar to that experienced with the iv drug.

Administration, Oral↗

PubMed1978

Pulmonary alveolar macrophage response to hyperbaric carbon monoxide exposure.

The sublethal effects of carbon monoxide (CO) in hyperbaric environments have not been adequately characterized. A physiologically sensitive indicator of sublethal effects of a contaminant is the pulmonary alveolar macrophage (PAM). The guinea pig PAM and its reaction to various CO concentrations at 8 atmospheres absolute (ATA) and the surface-equivalent concentrations at 1 ATA were studied in this experiment. In the absence of CO, PAM counts and viabilites from guinea pigs exposed to a helium-oxygen environment at either 1 or 8 ATA were not significantly different from one another. Mean PAM viability for guinea pigs exposed to CO concentrations at 2250--4200 mg/m3 at 8 ATA was 68.4 +/- 7.3% and was not significantly different from the 1-ATA viability value of 72.0 +/- 4.5% for the 1600--4200 mg/m3 CO range. The data show that at 1 to 8 ATA and CO concentrations of 1600--4200 mg/m3, the decrease in PAM viability was accompanied by dramatic five- to sixfold increases in PAM counts.

Animals↗

PubMed1977

Lymphoproliferative responses to antigens mediated by human pulmonary alveolar macrophages.

We evaluated the ability of human pulmonary alveolar macrophages (PAMs) to mediate (3H)-thymidine incorporation by blood lymphocytes severely depleted of monocytes when stimulated with soluble microbial and allogeneic lymphocyte antigens. Low (less than 2%) concentrations of PAM's from nonsmokers or blood monocytes did not support optimal responses. Over all, at greater than or equal to 10% concentrations, PAM's from nonsmokers supported higher responses than monocytes. At less than or equal to 10% concentrations, PAM's from heavy cigarette smokers mediated significantly less incorporation than did similar concentrations of PAM's from nonsmokers (p less than 0.05). The findings indicate that PAM's from healthy nonsmokers are functionally competent macrophages in terms of mediating lymphoproliferation in cultures stimulated with antigens. This classical macrophage function is impaired with cigarette smoking.

Adult↗

PubMed1977

Acid-base status in dietary treatment of phenylketonuria.

Blood acid-base status, serum electrolytes, and urine pH were examined in 64 infants and children with phenylketonuria (PKU) treated with three different low phenylalanine protein hydrolyzates (Aponti, Cymogran, AlbumaidXP) and two synthetic amino acid mixtures (Aminogran, PAM). The formulas caused significant differences in acid-base status, serum potassium, and chloride, and in urine pH. In acid-base balance studies in two patients with PKU, Aponti, PAM, and two modifications of PAM (P2 + P3) were given. We observed a change from mild alkalosis to increasing metabolic acidosis from Aponti (serum bicarbonate 25,8 mval/liter) to P3 (24,0Y, P2 (19, 3) and PAM (17,0). Urine pH decreased and renal net acid excretion increased. In the formulas PAM, P2 and P3 differences in renal net acid excretion correlated with differences in chloride and sulfur contents of the diets and of the urines. New modifications of AlbumaidXP and of PAM, prepared according to our recommendations, showed normal renal net acid excretion (1 mEq/kg/24 hr) in a balance study performed in one patient with PKU and normal acid base status in 20 further patients.

Acid-Base Equilibrium↗

PubMed1992

Studies of the amplification of carbaryl toxicity by various oximes.

The administration of 2-pyridine aldoxime methyl chloride (2-PAM Cl) is a standard part of the regimen for treatment of human overexposure to many organophosphorus pesticides and nerve agents. However, some literature references indicate that poisoning by carbaryl (1-naphthyl N-methyl carbamate), an insecticide in everyday use, is aggravated by the administration of 2-PAM Cl. This effect has been reported in the mouse, rat, dog and man. We have found that the inhibition of both eel acetylcholinesterase (eel AChE, EC 3.1.1.7) and human serum cholinesterase (human BuChE, EC 3.1.1.8) by carbaryl was enhanced by several oximes. Based on 95% confidence limits the rank order of potentiation with eel AChE was TMB-4 = Toxogonin > HS-6 = HI-6 > 2-PAM Cl. By the same criterion, the rank order of potentiation with human BuChE was TMB-4 > Toxogonin > HS-6 = 2-PAM Cl. Carbaryl-challenged mice also reflected a potentiation since TMB-4 exacerbated the toxicity more than 2-PAM Cl. Our hypothesis is that certain oximes act as allosteric effectors of cholinesterases in carbaryl poisoning, resulting in enhanced inhibition rates and potentiation of carbaryl toxicity.

Animals↗

PubMed1979

Application of a simple high-performance liquid chromatographic method for the determination of melphalan in the presence of its hydrolysis products.

A procedure for the separation and quantitation of melphalan (L-PAM) and its hydrolysis products by high-performance liquid chromatography is described. The hydrolysis of L-PAM at 25 +/- 0.1 degrees and 41 +/- 0.1 degrees was studied between pH 3.0 and 9.0. The pattern of hydrolysis suggested that L-PAM decomposes via two consecutive pseudo first-order reactions. Pseudo first-order rate constants (k1) were determined for the disappearance of L-PAM at various pH values in buffered solutions and in a formulated product. At both temperatures L-PAM solutions were found to be most stable at low pH. Chloride ion was found to reduce the rate of hydrolysis.

Chromatography, High Pressure Liquid↗

PubMed1977

Induction of aryl hydrocarbon hydroxylase in human pulmonary alveolar macrophages and peripheral lymphocytes by cigarette tars.

Cigarette smoking is associated with alterations in pulmonary alveolar macrophages (PAMs), including increased cytoplasmic inclusions and induction of the aryl hydrocarbon hydroxylase (AHH) system. Nonpigmented PAMs from nonsmokers were able to ingest and accumulate pigment from lysed PAMs of smokers, however, this pigment did not induce AHH activity in either PAMs or peripheral lymphocytes. In contrast, the cigarette tars significantly induced AHH levels in PAMs and in peripheral lymphocytes from either nonsmokers or smokers. This provides further evidence that components in cigarette smoke can explain the in vivo induction of AHH documented in cells from smokers.

Aryl Hydrocarbon Hydroxylases↗

PubMed1979

Phagocytosis of asbestos fibers by human pulmonary alveolar macrophages.

Human pulmonary alveolar macrophages (PAMs) were cultured for 24--72 h with varying concentrations (0--300 microgram/ml) of amosite asbestos (AS). At lower AS concentrations, (less than 100 microgram/ml) no decrease in cell viability occurred during the first 24 h of culture. Significant cytotoxicity (P less than 0.005 in all instances) was observed, however, following incubation for 24 h with higher AS concentrations (greater than 100 microgram/ml). Even following incubation with lower concentrations of AS, significant cytotoxicity (P less than 0.006 in all instances) was observed after 48 or 72 h of culture. Scanning electron microscopy (SEM) clearly illustrates the various stages of AS phagocytosis by PAMs. SEM also documented morphological changes in PAMs following AS exposure. These included increased zeiosis and the appearance of a fibrous-like material on the surface of AS fibers following initial contact with the PAM cytoplasmic membrane. Further study of the biological interactions between AS and human cells, such as PAMs, might provide valuable information regarding the etiology of AS-related lung disorders.

Adult↗

PubMed1976

Improved delivery through biological membranes. 2. Distribution, excretion, and metabolism of N-methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride, a pro-drug of N-methylpyridinium-2-carbaldoxime chloride.

N-Methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride, the pro-drug of 2-PAM, was found to be converted in vivo to 2-PAM, rapidly and quantitatively. The significantly changed properties of the pro-2-PAM resulted in a longer biological half-life and a favorable distribution of 2-PAM formed upon its oxidation. No new metabolite was found when pro-2-PAM was administered intravenously; however, a new metabolic product was formed when the pro-drug was given by oral route.

Administration, Oral↗