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PubMed2000

Allograft with unrelated donor accentuates the gastrointestinal toxicity associated with high-dose melphalan and total body irradiation preparative for bone marrow transplantation in children.

The use of high-dose melphalan (L-phenyalalanine mustard or L-PAM) has been shown to be associated with both hematological and non-hematological toxicity. It has been employed in the conditioning for allogeneic stem cell transplants from related donors but experience on its use in the unrelated setting has not been reported. As an attempt to elucidate the role of high-dose L-PAM (210 mg/m2) and total body irradiation (TBI) as a preparative regimen for allogeneic marrow transplantation from matched unrelated donors, they were employed in an institutional pilot series of seven pediatric patients. When compared with recipients of unrelated marrow grafts conditioned using other regimens, those treated with high-dose L-PAM experienced a markedly more severe acute graft-vs.-host disease (GvHD). The overall incidence of grade III-IV acute GvHD was higher (86% vs. 14%) among those treated with L-PAM. As judged by gastrointestinal (GI) symptoms, clinically significant (stages +2 to +4) gut GvHD was strikingly more prevalent among those treated with L-PAM (86% vs. 9%, p < 0.005). Toxic mortality prior to day + 100 was 29% in the L-PAM group and 9% in the non-L-PAM group of patients. With a mean follow-up of 21 months no increase in the incidence of chronic GvHD has been encountered among those conditioned with L-PAM. We conclude that the use of preparative L-PAM for allogeneic transplants from unrelated donors is associated with considerable procedure-related toxicity. We strongly suggest its use in this setting to be viewed with caution.

Antineoplastic Agents, Alkylating↗

PubMed1984

Enhancement of melphalan-induced tumour cell killing by misonidazole: an interaction of competing mechanisms.

In the present studies we have used the RIF-1 tumour in C3H mice to try to identify the mechanism(s) responsible for the enhancement of melphalan (L-PAM) induced tumour cell killing by the 2-nitroimidazole misonidazole (MISO). Most of this work was done with a single large dose of MISO (750 mg kg-1) given 30 min before injection of L-PAM. We found no effect of MISO on the repair of L-PAM-induced potentially lethal damage (PLD) as measured using an in vitro clonogenic survival assay. However, we identified three interrelated and competing processes which affect tumour cell killing by L-PAM subsequent to MISO injection. First, MISO reduces the clearance rate of L-PAM from the blood, an effect which enhances the cell killing by L-PAM. Second, MISO reduces the body temperature which produces a significant reduction in L-PAM cytotoxicity. Third, there is an enhancement of L-PAM cell killing by MISO over and above these two competing processes which is probably a result of the same mechanism by which cells in vitro are sensitized to L-PAM by pre-exposure to MISO under hypoxic conditions.

Animals↗

PubMed1983

Alterations in rat pulmonary macrophage function by the immunosuppressive agents cyclosporine, azathioprine, and prednisolone.

Disturbances of the immune response of the lung induced by the action of immunosuppressive agents on the functional abilities of rat pulmonary alveolar macrophages (PAM) were analyzed following in vitro incubation or in vivo administration (for 30 days) of cyclosporinea, (CsA) azathioprine (Az) or prednisolone (Pr). Two major parameters were analyzed: oxygen consumption and superoxide release as indices of the overall state of oxygen metabolism of these cells reflecting the integrity of PAM oxidative mechanisms of microbicidal activity, and chemotaxis, an event clinically important for normal defense to infection. In vitro incubation with cyclosporine at concentrations as low as 10(-9) M caused a 52% inhibition of PAM superoxide release, but Az had no effect at concentrations up to 10(-6) M. Prednisolone caused a 38% inhibition of superoxide release; comparable levels of inhibition with Pr required concentrations at least 10-fold greater than with cyclosporine. Further experiments indicated that cyclosporine induced a 40% inhibition after contact with PAM for only 30 min. In vivo experiments indicated that cyclosporine (5 mg/kg), Az (20 mg/kg), or Pr (2 or 0.5 mg/kg) administered intraperitoneally had no effect on the number of PAM available for host defense, PAM oxygen consumption, or PAM superoxide release. However, PAM from cyclosporine-treated animals demonstrated complete inhibition of active migration or chemotaxis in modified Boyden chambers upon incubation with formylmethionyl-leucyl-phenylalanine (FMLP). The effect was apparently dampened by simultaneous administration of Pr with cyclosporine. These experiments suggest that with the exception of a marked effect on chemotaxis the in vivo effects of physiologic amounts of cyclosporine on PAM function are modest compared with the marked depression after in vitro addition.

Animals↗

PubMed2004

Validity of the prosthetic activity monitor to assess the duration and spatio-temporal characteristics of prosthetic walking.

The prosthetic activity monitor (PAM) is an instrument to assess over the long-term the duration and spatio-temporal characteristics of walking of amputees, during normal daily life. In this study, the validity of PAM-derived measurements was investigated. Twelve transtibial amputees performed an activity protocol, consisting of stationary and walking activities, and activities associated with nonlocomotor movements. The protocol also included potential sources of error and activities assumed to be prone to misdetection. Measurements consisted of the PAM and video recordings. Agreement between video analysis and PAM output was the main outcome measure. The PAM generally correctly classified stationary activities (100% inactive, 0% active, 0% locomotion), nonlocomotor activities (45% inactive, 55% active, 0% locomotion) and walking activities (0% inactive, 1.8% active, 98.2% locomotion). When walking, the number of strides taken was slightly underestimated (-1.0%). The underestimation of distance travelled (-6.2%) and walking speed (-5.8%) was greater. The agreement with video output decreased when the PAM was misaligned, when persons walked at a speed below the defined minimum speed, and when persons walked with crutches. The PAM provides valid data on activity classes and number of strides. Although the majority of the distance data was satisfactory, in some cases considerable differences were found between the PAM and the video data. The impact of alignment, walking speed, and use of assistive devices on the PAM's operation should be considered.

Activities of Daily Living↗

PubMed1991

One hour in 1 ATA oxygen enhances rat alveolar macrophage chemiluminescence and fungal cytotoxicity.

The purpose of this study was to determine if 100% O2 would enhance rat pulmonary alveolar macrophage (PAM) oxidative killing of conidia of the fungus Neurospora crassa. First, we found that incubation in 100% O2 had no effect on conidia viability in the absence of PAM. We obtained resident PAM from nonpretreated anesthetized male Sprague-Dawley rats by bronchoalveolar lavage. Compared with similar air exposures we found that 1 h in vitro exposure of PAM to 100% O2 (1.0 atmosphere absolute) increased their killing of opsonized phagocytized conidia by 52%, without altering phagocytosis. A reactive oxygen killing mechanism is suggested because 1) 100% O2 increased PAM chemiluminescence (CL) by 60% both at rest and during 1 h of phagocytosis, and 2) PAM in 100% O2 killed albino conidia (lacking free radical-quenching carotenoids) 2.9 times more readily than they killed wild-type conidia. Compared with air, 100% O2 delayed the PAM respiratory burst time to peak by 18% but did not alter the burst maximal acceleration. The latter and the similar 60% increase in PAM CL in 100% O2 both at rest and during 1 h of phagocytosis suggests a nonenzymatic O2 enhancement of the respiratory burst. Changed timing of burst events in 100% O2 suggests early O2 toxicity. We conclude that 1 h in 100% O2 increases PAM free radical production and fungicidal activity.

Animals↗

PubMed1989

The effect of acute inflammatory lung injury on the respiratory burst and protein kinase C activity of rat pulmonary alveolar macrophages.

After induction of acute inflammatory lung injury in rats, unstimulated and zymosan-stimulated pulmonary alveolar macrophages (PAM) in suspension consumed significantly greater amounts of oxygen than did comparably stimulated PAM from noninjured lungs. Although oxygen consumption by PAM from injured lungs after stimulation with phorbol 12-myristate 13-acetate (PMA) was increased, it was not significantly different from that of PMA-stimulated PAM fron noninjured lungs. Despite the enhanced oxygen consumption, PAM from injured lungs in suspension did not secrete more superoxide (O2-) than did comparably stimulated PAM from noninjured lungs. It has been suggested that the respiratory burst in human polymorphonuclear leukocytes (PMN) and monocytes is dependent on the translocation of protein kinase C (PKC). We established that PKC was present in rat PAM and that acute lung injury did not alter total PKC activity or the subcellular distribution of the enzyme. Similarly, stimulation of PAM from noninjured lungs (zymosan, PMA) or injured lungs (zymosan) did not result in translocation of PKC activity, despite an enhanced oxidative burst. These results indicate that although PKC activity was present in PAM, translocation of PKC activity was not necessary for the respiratory burst.

Acute Disease↗

PubMed2005

Colonic Paneth cell metaplasia is pre-neoplastic condition of colonic cancer or not?

ABSTRACTS: BACKGROUND: The carcinogenesis of colorectal cancer has been accepted by a model for a cascade of genetic alterations, named the adenoma-carcinoma sequence. In order to elucidate the carcinogenesis of the colorectal cancer more clearly, the genetic abnormalies of the non-neoplastic mucosal epithelium of the colon and rectum should be investigated. It has been speculated that colonic Paneth cell metaplasia (PaM) is one of the pre-neoplastic mucosa of colonic cancer. Therefore, we studied the propria mucosa of the right colon with PaM from the standpoints of the frequency of the K-ras codon 12 mutations (K-ras), which is initial genetic abnormality in colorectal cancer, and the loss of heterozygosity of microsatellite markers (LOH-MS), which has a relationship to development of colorectal cancer. METHODS: Fifty-two regions with PaM histopathologically from 12 surgically resected right colon specimens were studied. DNA extraction of the colonic mucosa with PaM was obtained using a microdissection method, and the frequency of the K-ras of PaM was investigated by enriched polymerase chain reaction-enzyme linked mini-sequence assay, and the frequency of the LOH-MS (D2S123, D17S250 and D5S346) of PaM was examined by high resolution fluorescenced labeled PCR primers. RESULTS: K-ras mutation was detected in fifteen regions among 52 PaM (28.9%). All mutations were a single mutation and GGT changed to AGT in eleven and GAT in four. LOH-MS were detected in twenty-one regions among 52 PaM (40.4%) (D2S123: 35.4%, 17/48 regions, D17S250: 13.7%, 7/51 regions, and D5S346: 0%, 0/52 regions). No K-ras mutations and LOH-MS were detected in the controls (Colorectal mucosa with no PaM). CONCLUSIONS: Colonic mucosa with Paneth cell metaplasia may be one of the pre-neoplastic mucosa in the development of the colonic epithelial neoplasia.

Journal Article↗

PubMed1992

The multifunctional peptidylglycine alpha-amidating monooxygenase gene: exon/intron organization of catalytic, processing, and routing domains.

Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) is a multifunctional protein containing two enzymes that act sequentially to catalyze the alpha-amidation of neuroendocrine peptides. Peptidylglycine alpha-hydroxylating monooxygenase (PHM) catalyzes the first step of the reaction and is dependent on copper, ascorbate, and molecular oxygen. Peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) catalyzes the second step of the reaction. Previous studies demonstrated that alternative splicing results in the production of bifunctional PAM proteins that are integral membrane or soluble proteins as well as soluble monofunctional PHM proteins. Rat PAM is encoded by a complex single copy gene that consists of 27 exons and encompasses more than 160 kilobases (kb) of genomic DNA. The 12 exons comprising PHM are distributed over at least 76 kb genomic DNA and range in size from 49-185 base pairs; four of the introns within the PHM domain are over 10 kb in length. Alternative splicing in the PHM region can result in a truncated, inactive PHM protein (rPAM-5), or a soluble, monofunctional PHM protein (rPAM-4) instead of a bifunctional protein. The eight exons comprising PAL are distributed over at least 19 kb genomic DNA. The exons encoding PAL range in size from 54-209 base pairs and have not been found to undergo alternative splicing. The PHM and PAL domains are separated by a single alternatively spliced exon surrounded by lengthy introns; inclusion of this exon results in the production of a form of PAM (rPAM-1) in which endoproteolytic cleavage at a paired basic site can separate the two catalytic domains. The exon following the PAL domain encodes the trans-membrane domain of PAM; alternative splicing at this site produces integral membrane or soluble PAM proteins. The COOH-terminal domain of PAM is comprised of a short exon subject to alternative splicing and a long exon encoding the final 68 amino acids present in all bifunctional PAM proteins along with the entire 3'-untranslated region. Analysis of hybrid cell panels indicates that the human PAM gene is situated on the long arm of chromosome 5.

Animals↗

PubMed2001

Mechanism of melphalan-induced B7-1 gene expression in P815 tumor cells.

We have previously shown that exposure of P815 tumor cells to melphalan (L-phenylalanine mustard; L-PAM) leads to up-regulation of B7-1 surface expression, and this L-PAM-induced up-regulation requires de novo RNA synthesis and is associated with accumulation of B7-1 mRNA. Here we show that the effect of L-PAM on B7-1 surface expression can be mimicked by exposing P815 tumor cells to oxidative stress but not to heat shock. Moreover, the antioxidant N-acetyl-L-cysteine prevented the L-PAM-induced accumulation of B7-1 mRNA in P815 tumor cells, suggesting that reactive oxygen species are involved in the transcriptional regulation of L-PAM-induced B7-1 gene expression. Although AP-1 and NF-kappaB are regarded as redox-sensitive transcription factors and the promoter/enhancer region of the B7-1 gene contains an AP-1 and an NF-kappaB binding site, exposure of P815 tumor cells to L-PAM led to rapid and transient activation only of NF-kappaB, but not AP-1, that bound specifically to a probe containing the respective binding site in the murine or human B7-1 gene. Moreover, exposure of P815 tumor cells to a cell-permeable peptide that selectively inhibits NF-kappaB activation by blocking the activation of the IkappaB-kinase complex was found to inhibit the L-PAM-induced B7-1 mRNA accumulation, indicating that NF-kappaB activation is essential for the L-PAM-induced B7-1 gene expression. Taken together, these results indicate that L-PAM leads to activation of B7-1 gene expression by activating NF-kappaB via a pathway that involves reactive oxygen species.

Acetylcysteine↗

PubMed2001

Melphalan-induced expression of IFN-beta in MOPC-315 tumor-bearing mice and its importance for the up-regulation of TNF-alpha expression.

We have previously shown that administration of a low-dose of melphalan (L-phenylalanine mustard; L-PAM) to mice bearing a large s.c. MOPC-315 tumor leads to up-regulation of TNF-alpha expression, which is first evident at the mRNA level at 24 h after the chemotherapy. In this study, we show accumulation of IFN-beta mRNA in the spleen and tumor nodule of such mice as early as 1 h after the chemotherapy followed by elevated production of IFN-beta protein. IFN-beta protein in turn was found to be important for the L-PAM-induced up-regulation of TNF-alpha expression, as neutralization of IFN-beta inhibited the L-PAM-induced up-regulation of TNF-alpha mRNA expression in MOPC-315 tumor cells. In addition, L-PAM failed to up-regulate TNF-alpha expression in spleen cells from mice in which signaling by IFN-beta is deficient. Studies into the mechanism through which L-PAM leads to rapid accumulation of IFN-beta mRNA revealed that it requires de novo RNA synthesis, indicating that the regulation is at the transcriptional level. However, it did not require de novo protein synthesis, indicating that activation of pre-existing transcription factors is sufficient for IFN-beta gene expression. The L-PAM-induced accumulation of IFN-beta mRNA was mimicked with H(2)O(2) and was prevented with the antioxidant N-acetyl-L-cysteine, indicating that reactive oxygen species are involved in the transcriptional regulation of L-PAM-induced IFN-beta gene expression. Thus, the IFN-beta gene is an early response gene that is activated in response to L-PAM via a pathway that involves reactive oxygen species, and IFN-beta in turn plays an important role in L-PAM-induced TNF-alpha up-regulation.

Animals↗

PubMed1988

Importance of Lyt-2+ T-cells in the resistance of melphalan-cured MOPC-315 tumor bearers to a challenge with MOPC-315 tumor cells.

We have previously shown that mice bearing a large MOPC-315 tumor can be cured by a low dose of melphalan (L-phenylalanine mustard; L-PAM) if T-cell-dependent antitumor immunity also aids in tumor eradication (S. Ben-Efraim et al., Cancer Immunol. Immunother., 15: 101-107, 1983). Here we describe the phenotype of the T-cells that are responsible for the potent antitumor immunity exhibited by the L-PAM cured MOPC-315 tumor bearers. Initially, we identified the subset of T-cells responsible for the ability of spleen cells from L-PAM-cured MOPC-315 tumor bearers to neutralize tumor growth in the local adoptive transfer assay. The tumor-neutralizing activity of spleen cells from L-PAM-cured tumor bearers was drastically reduced when the spleen cells were depleted either in vitro or in vivo of Lyt-2+ cells. On the other hand, the tumor-neutralizing activity of spleen cells from L-PAM-cured MOPC-315 tumor bearers was not reduced, but actually enhanced, when the spleen cells were depleted either in vitro or in vivo of L3T4+ cells. The Lyt-2+ T-cells, and not the L3T4+ T-cells, were also found to be important for the ability of the intact L-PAM-cured MOPC-315 tumor bearers to reject a challenge with MOPC-315 tumor cells. Specifically, treatment of L-PAM-cured MOPC-315 tumor bearers with monoclonal anti-Lyt-2.2 antibody drastically reduced the ability of the mice to reject the tumor challenge. In contrast, treatment of the L-PAM-cured MOPC-315 tumor bearers with monoclonal anti-L3T4 antibody did not interfere with the ability of the mice to reject the tumor challenge, yet the same protocol of anti-L3T4 antibody treatment abolished the ability of splenic T-cells to provide help for the generation of a primary T-cell-dependent antibody response. The resistance of the L-PAM-cured MOPC-315 tumor bearers to challenge with MOPC-315 tumor cells was also dependent on the participation of carrageenan-sensitive effector cells, most likely macrophages, in tumor eradication. However, the immunity mediated by the T-cells, independent of carrageenan-sensitive effector cells, was extremely powerful and sufficient for the rejection of a tumor challenge with at least 300-fold, and possibly even 3000-fold, the minimal lethal dose of MOPC-315 tumor cells for 100% of normal mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Cytokine modulation of the immunosuppressive phenotype of pulmonary alveolar macrophage populations.

Under steady-state conditions, T-cell activation in the lung is tightly controlled by lymphocytostatic signals from resident pulmonary alveolar macrophages (PAM). The present study focuses upon the mechanism of suppression in the mouse, and how it is bypassed during local inflammatory challenge. Reactive nitrogen intermediates such as nitric oxide (NO) are shown to play a central role in the process as the expression of lymphocytostatic activity by resident murine PAM was abrogated by the NO synthetase inhibitor N-monomethyl-arginine. Overnight pretreatment of resident PAM with granulocyte-macrophage colony-stimulating factor (GM-CSF) abrogated lymphocytostatic activity, with a concomitant small decrease in NO production; this effect was markedly amplified by tumour necrosis factor-alpha (TNF-alpha), but the latter was ineffective alone. The cytokines were inactive if added singly or in combination to fresh PAM:T-cell co-cultures. If GM-CSF plus TNF-alpha exposure of PAM was prolonged beyond 48 hr, both lymphocytostatic and NO-producing capacity were spontaneously re-established. Transforming growth factor-beta (TGF-beta) also inhibited both NO production and lymphocytostatic activity of PAM, but in contrast to GM-CSF and TNF-alpha, TGF-beta was only active if present throughout the PAM:T-cell coculture period. Additionally, monocytes recruited into the lung by a sterile inflammatory stimulus are shown to be initially stimulatory towards T-cell activation, and to progressively develop both T-cell suppressive- and NO synthetic-capacity as they mature into mature PAM in vivo. Thus, during acute lung inflammation, a series of overlapping mechanisms are potentially available to bypass local immunosuppression: secretion of cytokines which are capable of temporarily abrogating the immunosuppressive activity of resident PAM, and the recruitment of permissive monocytes which exhibit potent accessory cell activity, the net result being the creation of a transient 'window' for induction of local T cell-mediated immunity.

Animals↗

PubMed1993

Peptidylglycine alpha-amidating monooxygenase: a multifunctional protein with catalytic, processing, and routing domains.

Peptide alpha-amidation is a widespread, often essential posttranslational modification shared by many bioactive peptides and accomplished by the products of a single gene encoding a multifunctional protein, peptidylglycine alpha-amidating monooxygenase (PAM). PAM has two catalytic domains that work sequentially to produce the final alpha-amidated product peptide. Tissue-specific alternative splicing can generate forms of PAM retaining or lacking a domain required for the posttranslational separation of the two catalytic activities by endoproteases found in neuroendocrine tissue. Tissue-specific alternative splicing also governs the presence of a transmembrane domain and generation of integral membrane or soluble forms of PAM. The COOH-terminal domain of the integral membrane PAM proteins contains routing information essential for the retrieval of PAM from the surface of endocrine and nonendocrine cells. Tissue-specific endoproteolytic processing can generate soluble PAM proteins from integral membrane precursors. Soluble PAM proteins are rapidly secreted from stably transfected nonneuroendocrine cells but are stored in the regulated secretory granules characteristic of neurons and endocrine cells.

Alternative Splicing↗

PubMedDate not supplied

Synthetic S-(2,3-dihydroxypropyl)-cysteinyl peptides derived from the N-terminus of the cytochrome subunit of the photoreaction centre of Rhodopseudomonas viridis enhance murine splenocyte proliferation.

Various lipopeptides representing the N-terminal part of the cytochrome subunit of the photosynthetic reaction centre from the purple bacterium Rhodopseudomonas virdis were prepared by solid-phase peptide synthesis. These lipopeptides consisted of a S-[2,3-dihydroxypropyl]-cysteinyl (Dhc) residue N-terminally coupled to the nonapeptide FEPPPATTT. Different numbers of palmitoyl (Pam) chains were attached to Dhc via ester and/or amide bonds. The lipopeptide Dhc(Pam)2-FEPPPATTT containing two ester-bonded palmitoyl residues and a free N-terminus was a potent polyclonal activator of murine (BALB/c) spleen cells at subnanomolar concentrations. The lipopeptide Pam-Dhc(Pam)2-FEPPPATTT containing three palmitoyl residues, the two-chain lipopeptide Pam-Dhc(Pam)-FEPPPATTT containing one amide- and one ester-bonded palmitoyl residue, and the N-terminally elongated lipopeptide SLVAG-Dhc(Pam)2-FEPPPATTT were less active. The nonapeptide FEPPPATTT and the decapeptide Dhc-FEPPPATTT were only marginal splenocyte activators, even at concentrations as high as 1 microM. Thus, lipopeptide Dhc(Pam)2-FEPPPATTT constitutes the first potent splenocyte stimulation Dhc-lipopeptide described so far that contains only two fatty acid residues.

Adjuvants, Immunologic↗

PubMed2000

Induction of peptidylglycine alpha-amidating monooxygenase in N(18)TG(2) cells: a model for studying oleamide biosynthesis.

The fatty-acid primary amide, oleamide, is a novel signaling molecule whose mechanism of biosynthesis is unknown. Recently, the N(18)TG(2) cell line was shown to synthesize oleamide from oleic acid, thereby demonstrating that these cells contain the necessary catalytic activities for generating the fatty-acid primary amide. The ability of peptide alpha-amidating enzyme, peptidylglycine-alpha-amidating monooxygenase (PAM; EC 1.14.17.3), to catalyze the formation of oleamide from oleoylglycine in vitro suggests this as a function for the enzyme in vivo. This investigation shows that N(18)TG(2) cells, in fact, express PAM and that cellular differentiation dramatically increases this expression. PAM expression was confirmed by the detection of PAM mRNA, PAM protein, and enzymatic activity that exhibits the functional characteristics of PAM isolated from mammalian neuroendocrine tissues. The regulated expression of PAM in N(18)TG(2) cells is consistent with the proposed role of PAM in the biosynthesis of fatty-acid primary amides and further establishes this cell line as a model for studying the pathway.

Animals↗

PubMed1994

Effect of arsenic exposure on alveolar macrophage function. I. Effect of soluble as(III) and as(V).

Despite potential differences in the mechanism and potency of toxicity between the two common oxidation states of arsenic (As(III) and As(V)), assessments of the risk from inhaled arsenic generally ignore the oxidation state of inorganic arsenicals. Differences between potency and toxicity of As(III) and As(V) were evaluated by determining alteration in function of pulmonary alveolar macrophages (PAM) following in vivo and in vitro exposure to soluble arsenic. Male Sprague-Dawley rats were used throughout. One day following intratracheal instillation of 1 mg/ml (as arsenic) of either sodium arsenite (As(III)) or sodium arsenate (As(V)), PAM were lavaged and analyzed for alterations in superoxide (O2-), prostaglandin E2 (PGE2), and tumor necrosis factor (TNF-alpha) production. There were no differences in bronchoalveolar lavage fluid PGE2 or TNF-alpha. PAM lavaged from As(V)-exposed animals showed significant increases in O2- production. In vivo exposure to either oxidative form of arsenic decreased basal and lipopolysaccharide (LPS)-induced release of TNF-alpha production by PAM, but did not suppress LPS-induced production of PGE2. To test the direct effects of arsenic on PAM function, PAM were lavaged from control animals and exposed, in vitro, to either arsenical for up to 24 hr to concentrations of 0.1 to 300 micrograms/ml arsenic. Doses used were not cytotoxic to PAM, since LDH release was not significantly increased, even at the highest dose. Significant dose-dependent inhibition of O2- production was only evident after 24 hr exposure to arsenicals. As(III) was more potent than As(V), inhibiting O2- at concentrations as low as 0.1 micrograms/ml compared to 1.0 micrograms/ml of As(V). Suppression of LPS-induced release of TNF-alpha also occurred at lower concentrations of As(III), 50% inhibition at 0.15 micrograms/ml, compared to As(V), 50% inhibition at 1.8 micrograms/ml. While As(III) exposure had no affect on PGE2 production, As(V) caused inhibition of LPS-induced PGE2 production at concentrations above 1.0 micrograms/ml. Differences between As(III) and As(V) indicate that different mechanisms and/or potencies exist between the two arsenic species. Arsenic-induced alteration in PAM function may compromise host defense against infections and alter immune surveillance.

Animals↗

PubMed1998

Immunotoxicologic effects of inhaled chromium: role of particle solubility and co-exposure to ozone.

Soluble and insoluble hexavalent chromium (Cr6+) agents are concomitantly released with ozone (O3) during welding. Although pulmonary/immunologic implications from exposure to each agent individually have been investigated, the effects from simultaneous exposure, as occurs under actual working conditions, are unclear. To investigate immunomodulatory effects of inhaled Cr6+, F-344 rats were exposed for 5 h/day, 5 days/week for 2 or 4 weeks to atmospheres containing soluble potassium chromate (K2CrO4) or insoluble barium chromate (BaCrO4), each alone at 360 micrograms Cr/m3 or in combination with 0.3 ppm O3. One day after the final exposure, rats were euthanized, their lungs were lavaged, and pulmonary macrophages (PAM) were recovered for assessment of basal and inducible functions. Rats inhaling K2CrO4-containing atmospheres had greater levels of total recoverable cells, neutrophils, and monocytes in bronchopulmonary lavage compared to rats exposed to insoluble Cr6+ atmospheres, O3 alone, or air; these rats also had a reduced percentage of PAM, although total PAM levels remained unaffected. Although Cr exposure-related changes in PAM functionality were evident, any dependence upon Cr solubility was variable. K2CrO4-containing atmospheres modulated PAM-inducible interleukins-1 and -6, and tumor necrosis factor-alpha production to a greater degree than those containing BaCrO4. Conversely, BaCrO4-containing atmospheres affected PAM basal nitric oxide production and interferon-gamma-primed/zymosan-stimulated reactive oxygen intermediate production to a greater extent than did those containing K2CrO4. In none of the PAM assays did co-inhalation of O3 result in a modulation of the effects obtained with either Cr6+ compound itself. The results indicate that, while immunomodulatory effects of inhaled Cr6+ upon PAM are related to particle solubility, the co-inhalation of O3 apparently does not cause further modifications of the metal-induced effects.

Administration, Inhalation↗

PubMed1994

Detection of gaps in sinusoids by frog auditory nerve fibers: importance in AM coding.

Physiological studies were carried out in the frog (Rana pipiens pipiens) eighth nerve to determine: (i) whether the modulation rate or the silent gap was the salient feature that set the upper limit of time-locking to pulsed amplitude-modulated (PAM) stimuli, (ii) the gap detection capacity of individual eighth nerve fibers. Time-locked responses of 79 eighth nerve fibers to PAM stimuli (at the fiber's characteristic frequency) showed that the synchronization coefficient was a low-pass function of the modulation rate. In response to PAM stimuli having different pulse durations, a fiber gave rise to non-overlapping modulation transfer functions. The upper cut-off frequency of time locking was higher when tone-pulses in PAM stimuli had shorter duration. The fact that the cut-off frequency was different for the different PAM series suggested that the AM rate was neither the sole, nor the main, determinant for the decay in time-locking at high AM rates. Gap detection capacity was determined for 69 eighth nerve fibers by assessing fiber's spiking activities to paired tone-pulses during an OFF-window and an ON-window. It was found that the minimum detectable gap of eighth nerve fibers ranged from 0.5 to 10 ms with an average of 1.23-2.16 ms depending on the duration of paired tone pulses. For each fiber, the minimum detectable gap was longer when the duration of tone pulses comprising the twin-pulse stimuli was more than four times longer. When the synchronization coefficient was plotted against the silent gap between tones pulses in the PAM stimuli, the gap response functions of a fiber as derived from multiple PAM series were equivalent to gap response functions deriving from twin-pulse series suggesting that it was the silent gap which primarily determined the upper limit of time-locking to PAM stimuli.

Acoustic Stimulation↗