Diffuse interstitial pneumonia and pulmonary hypertension: a novel manifestation of chronic granulomatous disease.

The present authors report the case of an adult with chronic granulomatous disease who developed an unusual lung fibrosis associated with severe pulmonary hypertension. Histological analysis of a lung biopsy showed a diffuse infiltration with pigmented macrophages without granulomas, which particularly involved the pulmonary arterial and venular walls. Clinical and histological findings were suggestive of pulmonary veno-occlusive disease. Such a clinical association has not been previously described in the literature and might be due to the persistent expression of gp91phox at a very low level. In conclusion, the present case report illustrates a novel manifestation of chronic granulomatous disease.

Potential role of the "NADPH oxidases" (NOX/DUOX) family in cystic fibrosis.

Cystic fibrosis (CF), is the most common life-shortening autosomal recessive disorder in Caucasians. It is caused by mutations in a single gene on the long arm of chromosome 7 that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CF is characterized by abnormal Na+ and Cl- ion transport in several tissues, including the lungs, pancreas, gastrointestinal tract, liver, sweat glands, and male reproductive system. Progressive pulmonary disease is the dominant clinical feature of CF and accounts for morbidity and mortality. The inflammation characterized by an overabundance of activated neutrophils and macrophages on the respiratory epithelial surface is associated to a high production of reactive oxygen species (ROS) which contribute to the pathogenesis of cystic fibrosis. ROS could have different origins but the role of the NADPH oxidase system is essential. The "NADPH oxidases" (NOX/DUOX) family is an enzymatic complex formed by cytosolic and membrane subunits. Until now several homologues of the phagocytic NADPH oxidase have been identified in different tissues and it has been shown that the lungs preferentially expressed DUOX1-2. Thus, DUOX1-2 could be implicated in the anti-infectious defense system. The role of DUOX enzymes as a source of ROS in cystic fibrosis is examined as they could contribute to a better understanding of molecular mechanisms in CF. Moreover they could be a potential target for a new therapeutic approach.

Interleukin-12 increases interleukin 8 production and release by human polymorphonuclear neutrophils.

Interleukin (IL) 12 is a heterodimeric cytokine mainly produced by phagocytes-important target cells for IL-12 in particular with a chemotactic effect-and antigen-presenting cells in response to various microorganisms. Because IL-8 is a strong chemokine for polymorphonuclear neutrophils (PMNs), we investigated the effect of IL-12 on PMN IL-8 production. IL-12 alone had no significant effect, but with lipopolysaccharide (LPS) it was additive at both protein and mRNA levels. Actinomycin D at the beginning of culture inhibited IL-8 mRNA induction, whereas late addition affected IL-8 transcript stability, suggesting gene transcription involvement. Results with parthenolide and tyrphostin AG490 suggest that nuclear factor-kappaB and signal transducer and activator of transcription 4 play a role. The IL-12 additive effect was restricted to IL-8 release, with no action on cell-associated IL-8. IL-12 additive effects occurred after 18 h of culture, with no marked up-regulation of IL-12 receptor expression, and were blocked by actinomycin D added after 16 h of culture. Tumor necrosis factor (TNF) alpha and interferon (IFN) gamma had intermediate roles; their specific inhibition reduced IL-12's effect. IL-12's chemotactic mechanism seemed mediated by overproduction and release of IL-8 by human PMNs in the presence of LPS, an effect involving TNF-alpha and IFN-gamma secretion. These results point to a new role for IL-12 in inflammation, through an autocrine amplification loop.

P40phox associates with the neutrophil Triton X-100-insoluble cytoskeletal fraction and PMA-activated membrane skeleton: a comparative study with P67phox and P47phox.

NADPH oxidase is an O2*- -generating enzyme found in phagocytes such as neutrophils. It is composed of a membrane-bound cytochrome b, the cytosolic proteins p67phox, p47phox, p40phox, and the G-protein p21rac. The system is dormant in resting cells but acquires catalytic activity on exposure to appropriate stimuli. Cytochrome b, p67phox, p47phox, and rac2 associate with the cytoskeleton and membrane skeleton of activated neutrophils. It is not known whether p40phox associates with the cytoskeleton. The purpose of this study was to analyze the subcellular distribution of p40phox. When resting neutrophils were lysed in Triton X-100 or octyl glucoside buffer and separated into detergent-soluble and detergent-insoluble fractions, p40phox and p67phox were mainly associated with the detergent-insoluble fraction (defined as the cytoskeleton), whereas p47phox was mainly found in the soluble fraction. Neutrophil activation by phorbol myristate acetate (PMA) induced p47phox translocation to the cytoskeleton but did not affect the distribution of p40phox or p67phox. Using immunofluorescence confocal microscopy, we found that p40phox colocalized with filamentous actin. In neutrophils from a p67phox-deficient patient with detectable p40phox, p40phox associated with the cytoskeleton only after activation by PMA. A complex containing the three proteins was isolated from the cytoskeleton of activated neutrophils. When activated membranes were treated with Triton X-100 buffer, p40phox, p47phox, and p67phox were found in the membrane skeleton enriched in NADPH-oxidase activity; some p40phox and p47phox was found in the soluble membrane fraction, but no p67phox was detected. These findings show that p40phox, like p67phox and p47phox, binds to the cytoskeleton and membrane skeleton. In addition, p40phox can dissociate from p67phox in activated membranes.

An intronic polymorphic repeat sequence modulates interleukin-1 alpha gene regulation.

Recently, we characterized a polymorphism within IL-1 alpha intron 6 as a variable number of a 46 bp tandem repeat (ranging from 5 to 18 repeats). We now analyse whether this polymorphism could play a role in IL-1 alpha gene regulation. We have found that reporter gene expression driven by the IL-1 alpha promoter or a heterologous promoter was decreased by increasing numbers of the repeat sequence corresponding to the most frequent alleles seen in the human population. Furthermore, we showed that the transcription factor Sp1 can bind to the 46 bp sequence. Finally, we were unable to show a statistically-significant relation between in vitro IL-1 alpha production and the number of repeats although there was a clear trend towards an inverse relation. Taken together, these results are consistent with a negative regulatory role for IL-1 alpha intron 6 repeat sequence on IL-1 alpha basal gene transcription.

Comparison of plasma cytokine levels in African patients with HIV-1 and HIV-2 infection.

OBJECTIVE: To determine plasma cytokine levels [tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6] in African patients infected with HIV-2 relative to values in HIV-1-infected patients, and their relation to immunologic and clinical status. DESIGN: Questions about the observed differences in the pathogenesis of HIV-2 and HIV-1 remain unanswered. Cytokines, especially TNF-alpha, are involved in the regulation of HIV-1 replication, and can be found in the plasma of HIV-1-infected individuals. Therefore, we evaluated TNF-alpha, IL-1 beta and IL-6 levels in the plasma of African patients with different stages of HIV-2 disease. This was a 3-year prospective follow-up study. METHODS: Cytokine plasma levels were assayed in 40 HIV-2- and 51 HIV-1-infected patients from Africa. Nineteen of the 40 HIV-2-infected-patients underwent serial assays every 4 months for 3 years. Data were analysed in relation to the number of CD4+ and CD8+ cells, viral load and clinical status. RESULTS: Plasma levels of TNF-alpha and IL-1 beta were significantly higher in all the HIV-1- and HIV-2-infected patients than in healthy controls; IL-6 levels were around the detection limit for all patients. TNF-alpha levels were lower in the HIV-2-infected than in the HIV-1-infected patients at all Centers for Disease Control and Prevention (CDC) disease stages, including the asymptomatic phase. The CD4+ cell count was always higher in the HIV-2-infected patients, regardless of CDC stage. The prospective follow-up showed that TNF-alpha levels remained stable during the course of HIV-2 disease, as did the CD4+ cell count and virus load. CONCLUSION: Lower and stable plasma TNF-alpha levels in African patients infected with HIV-2, associated with lower viral load and higher CD4+ cell count, suggests the existence of a more appropriate and efficient immune response to HIV-2 than to HIV-1.

Characterization of 11 novel mutations in the X-linked chronic granulomatous disease (CYBB gene).

The most frequent form of chronic granulomatous disease (CGD) is caused by inactivation of the CYBB gene, which encodes the gp91-phox subunit of phagocyte NADPH oxidase. This defect prevents phagocytes from producing reactive oxygen species and thus from eradicating bacterial and fungal infections. We investigated 16 unrelated male patients with suspected X-linked CGD and gp91-phox deficiency. A mutation was found in the CYBB gene of all 16 patients, and 11 of these mutations were novel. Eleven patients (69%) had a point mutation (84G>A in two unrelated patients, and 177C>G, 217C>T, 388C>T, 676C>T, 691C>T, 868C>T, 919A>C, 1384G>T and T1514G in one case each, yielding W28X, C59W, R73X, R130X, R226X, Q231X, R290X, T307P, E462X, L505R gp-91phox). One patient had an in-frame deletion removing two amino acids (R54 and A55). Finally, insertions or duplications were found in four patients (from +1 to +31 bases). Overall, 12 (75%) of the mutations led to the production of a truncated protein. No clear correlation was found between clinical manifestations and genomic/biochemical alterations. Thirteen mothers could be tested, and all were carriers. Hum Mutat 18:163, 2001.

Protective effect of LPS and poly A:U against immune oxidative injury: role of thiols released by activated macrophages.

Oxidative injury of immune cells has been observed both at inflammatory sites and in pathologic situations, such as human immunodeficiency virus infection. We used an ex vivo model of immune oxidative injury to test the antioxidant effect of two immunomodulating agents administered to C57B1/6 mice. Lipopolysaccharide (LPS) and the synthetic polyribonucleotide poly A:U preserved the ConA-induced proliferative response of spleen T cells against oxidative injury ex vivo. The glutathione and thiol contents of fresh spleen T cells from LPS- and poly A:U-treated mice were significantly higher than control values. In addition, spleen T cells from LPS- and poly A:U-treated mice were protected against the oxidative injury-induced decrease in glutathione content after 48 h of ConA stimulation. Because LPS and poly A:U both activate macrophages, we sought an antioxidant effect of macrophage-released compounds. Neither rhIL-1 alpha nor rhTNF alpha protected against oxidative injury in vitro. In contrast, LPS and poly A:U induced macrophages to release acid-soluble thiols, which have been reported to participate in the regulation of glutathione levels in lymphocytes and could therefore protect against immune oxidative injury.

Hydroxyl radical as a potential intracellular mediator of polymorphonuclear neutrophil apoptosis.

We investigated reactive oxygen species (ROS) involvement in polymorphonuclear neutrophilic leukocyte (neutrophil) apoptosis triggering. Neutrophils were incubated with xanthine oxidase (XO), which produces superoxide anion (O2.-) and hydrogen peroxide (H2O2) or glucose oxidase (GO), which produces only H2O2. Both XO and GO accelerated apoptosis when compared to spontaneously aged neutrophils. Catalase inhibited both spontaneous apoptosis and XO- or GO-accelerated apoptosis, but superoxide dismutase did not. Hydrogen peroxide can enter the cell, thus generating intracellular oxidation, which was observed by flow cytometry. Furthermore, the intracellular reduced glutathione content fell in the presence of XO or GO; however, apoptosis was not accelerated in the presence of buthionine sulfoximine (BSO), suggesting that the fall in glutathione in the presence of XO or GO is a consequence of oxidative stress but not a trigger of apoptosis. Hydrogen peroxide can react with iron to form hydroxyl radicals (HO.); we observed that two iron chelators, deferoxamine and hydroxybenzyl ethylenediamine (HBED), both inhibited spontaneous and accelerated apoptosis, suggesting that HO. may mediate neutrophil apoptosis.

Defective priming of the phagocyte oxidative burst in a child with recurrent intracellular infections.

Human phagocytes (polymorphonuclear neutrophils and monocytes) play a critical role in host defense against invading microorganisms. Recent studies reported that circulating phagocytes undergo a final maturation process, in particular in terms of oxidative burst, during extravasation and migration to local sites of inflammation. This process is known as priming. We report here on a nine-year-old boy with successive disseminated infections due to intracellular microorganisms (Mycobacterium bovis, BCG, and Salmonella typhimurium). No T- or B-cell quantitative or qualitative defects were found. Polymorphonuclear neutrophil (PMN) migration and NADPH oxidase in PMNs and monocytes stimulated with various agents at optimal concentrations were normal, ruling out a leukocyte adhesion deficiency syndrome, a Chediak Higashi syndrome, and a chronic granulomatous disease. Nevertheless, the patient's PMNs and monocytes showed defective priming capacity, as measured by H(2)O(2) production after pretreatment with LPS (5 microg/mL for 30 min), TNFalpha (100 units/mL for 30 min), or IL-8 (50 ng/mL for 30 min) in response to bacterial N-formyl peptides (fMLP 10(-6) M for 5 min). In these conditions, H(2)O(2) production of PMNs and monocytes from the patient did not exceed that of the samples treated with fMLP or LPS alone, while the controls strongly produced H(2)O(2). Moreover, monocytes from the patient showed an impaired capacity to kill S. typhimurium in vitro. Such an impairment could be related at least in part to the priming deficiency of phagocyte oxidative burst. This case suggests, for the first time, that in vivo priming processes are critical in host defence against intracellular pathogens.

Enumeration of the T4 positive and T8 positive lymphocytes in AIDS and related syndromes. Comparison of the immunogold and the immunofluorescence techniques.

Immunofluorescence and immunogold techniques yielded similar results when used to determine the T lymphocyte subsets (T4 and T8 positive cells) in patients with AIDS or AIDS-related complex and in healthy homosexual men seropositive for HTLV III/LAV antibody. In these pathological situations, the advantages of immunogold staining could render this technique useful in a clinical laboratory.

Increased CD1-positive cells in peripheral blood of AIDS and ARC patients.

CD1 monoclonal antibodies were assayed on peripheral blood mononuclear leukocytes (PBML) of type 1 human immunodeficiency virus (HIV1)-infected patients using immunogold technique. Using IOT6 monoclonal antibody, a significant increase of the CD1 positive cells per microliter of blood was found in acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) patients (265 +/- 34/microliters, n = 44 and 491 +/- 64/microliters, n = 36, respectively) as compared to controls (108 +/- 11/microliters, n = 43, P less than 0.001). These findings were confirmed with four other CD1 monoclonal antibodies in six patients. Characterisation of these CD1 positive cells showed that they were double stained with either CD4 or CD8 monoclonal antibodies. Moreover, cytochemical analysis of these cells showed the absence of myeloperoxidase activity and ultrastructural examination did not reveal Birbeck granules, well known to characterise the Langerhans cells. Further investigations are warranted to assess the biological and clinical relevance of these findings.

Appraisal of potential therapeutic index of antioxidants on the basis of their in vitro effects on HIV replication in monocytes and interleukin 2-induced lymphocyte proliferation.

Antioxidant molecules have been suggested to be of therapeutic value in the treatment of HIV-infected patients. To evaluate this possibility, we examined in vitro the effects of two types of antioxidant molecules in terms of inhibition of HIV replication in monocytes, one of the main reservoirs of HIV, and also in terms of modulation of the immune competence as measured by PBMC proliferation. We tested the effects of BHA, a phenolic, lipid-soluble, chain-breaking antioxidant, and NAC, a known glutathione precursor with some direct free-radical scavenging properties as well, on the regulation of HIV-1 expression in latently infected U1 cells and in productively and chronically infected U937 cells. Both antioxidants inhibited TNF- or PMA-induced NF-kappa B activity in U1 cells, as well as the sustained NF-kappa B activity permanently induced by the virus itself in chronically HIV-infected U937 cells. This resulted in only a partial inhibition of TNF- or PMA-induced HIV replication in U1 cells, and no detectable effect on HIV replication in chronically infected U937 cells. This may be the first limitation to potential antiviral effects of antioxidant therapies. Another limitation is that antioxidant concentrations high enough to block NK-kappa B activation were shown to have a suppressive effect on immune functions in vitro, because NAC and BHA blocked IL-2-induced PBMC proliferation. These data warrant prudence in the design of antioxidant-based therapies aimed at suppressing HIV replication.

Effect of doxycycline on oxygen-dependent killing mechanisms of human neutrophils.

The effects of doxycycline on neutrophil adhesivity, ingestion rate, and oxidative burst by particle and soluble compounds have been analyzed. The rate of bacterial ingestion by neutrophils as well as its subsequently particle-induced oxidative burst comprising oxygen uptake, hydrogen peroxide and superoxide anion productions, and iodination were all inversely correlated to doxycycline concentration included in the assay medium. The neutrophil oxidative burst induced by phorbol myristate (a soluble stimulant) was also inversely correlated to doxycycline concentration. Drug effect was observed at lower concentrations when the neutrophil stimulant was a soluble compound than when it was particles. In contrast doxycycline did not affect neutrophil adhesivity to either nylon fibers or Petri dishes. Further studies are needed to assess whether the activity of the drug on the neutrophil is due only to its ability to chelate calcium and magnesium or to other properties.

Diclofenac binding to human polymorphonuclear neutrophils: effect on respiratory burst and N-formylated peptide binding.

The respiratory burst of human polymorphonuclear neutrophils (PMN) induced by particle or soluble stimuli was measured in the presence of the nonsteroidal anti-inflammatory drug, diclofenac sodium (Voltaren). Diclofenac (25-100 micrograms/ml) inhibited the oxygen consumption of PMN stimulated by 5 X 10(-7) M of N-formyl-methionyl-leucyl-phenylalanine (FMLP). The inhibition was linearly correlated to diclofenac concentration. By contrast, diclofenac did not affect the rate of heat-killed Klebsiella pneumoniae ingestion of PMN, or the PMN O2-uptake induced by (0.67 microgram/ml) serum-opsonized zymosan or (1 microgram/ml) phorbol myristate acetate (PMA). The PMN production of superoxide anion induced by various FMLP concentrations (10(-7), 10(-6) and 10(-5) M) was also decreased by diclofenac. However, this inhibition declined when the formylated peptide concentration was raised suggesting that diclofenac could alter FMLP binding to the PMN membrane. Binding experiments of tritiated FMLP to intact PMN performed at 22 degrees and 4 degrees showed high- and low-affinity FMLP sites with dissociation constant (Kd) values of approximately 2 X 10(-8) M and 10(-5) M respectively. Diclofenac did not significantly alter the low-affinity component but induced modifications of the high-affinity component which were different at 22 degrees and 4 degrees. At 22 degrees only the dissociation constant value was enhanced by diclofenac (competitive inhibition) whereas at 4 degrees both binding parameters (i.e. dissociation constant and number of available binding sites) were modified (mixed inhibition). Diclofenac was also shown to bind to PMN with a low affinity. This binding was not diminished at 4 degrees by various concentrations of FMLP which even increased the number of diclofenac binding sites on PMN at 22 degrees. These data suggest that diclofenac binding to PMN may decrease FMLP-induced PMN respiratory burst by interfering with the peptide recognition by specific FMLP receptors.

Diclofenac sodium, a negative chemokinetic factor for neutrophil locomotion.

Diclofenac sodium, a non steroidal anti-inflammatory agent, was studied for its influence on the locomotion of human polymorphonuclear neutrophils (PMN), in an attempt to define the mechanism governing the drug's anti-inflammatory properties. PMN locomotion was measured by the agarose technique under two conditions of stimulation of cell migration: in the presence of a gradient of stimuli (chemotaxis) and in the presence of various amounts of stimuli incorporated in the gel (chemokinesis). At concentrations below 10 micrograms/ml, diclofenac in the gel reduced, in a dose-dependent manner, the directed locomotion of PMN induced by a gradient of C5a-activated serum, peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) or Klebsiella pneumoniae culture supernatant (KPCS). Diclofenac also inhibited the random locomotion of unstimulated PMN, as well as the PMN chemokinetic activity induced by various amounts of FMLP or activated serum. Inhibition of PMN locomotion by diclofenac decreased when the concentration of the stimulant was raised; this inhibition was inversely related to the concentration of heat-inactivated fetal calf serum in the medium. The directed locomotion and chemokinesis of PMN, induced by FMLP were also reduced in PMN preincubated with diclofenac before migration, suggesting a direct cellular effect of diclofenac. On the other hand, diclofenac did not affect the changes in shape induced in floating PMN by FMLP or activated serum. The observation that diclofenac did not alter the ingestion rate of bacteria by PMN indicates that this drug is not cytotoxic for PMN. Consequently, diclofenac reduces PMN locomotion by interfering with the PMN chemokinetic activity. Diclofenac is an anti-inflammatory drug possessing the original property of acting as a negative chemokinetic agent, for migration of both stimulated and unstimulated PMN. It should therefore be a useful tool for analyzing the elements controlling PMN locomotion speed.

Alveolar neutrophil oxidative burst and beta2 integrin expression in experimental acute pulmonary inflammation are not modified by inhaled nitric oxide.

It was recently proposed that nitric oxide (NO) inhalation interferes with polymorphonuclear neutrophil (PMN) activation status during acute pulmonary inflammation, although variable results have been observed considering timing of NO administration, species, and model differences. After intratracheal administration of lipopolysaccharide (LPS) in rats, we characterized pulmonary inflammatory reaction (lung wet, dry, and wet to dry weights) and, using flow cytometry, the activation status (H2O2 production and beta2 integrin CD11b/CD18 expression) of PMN obtained from blood and from bronchoalveolar lavage (BAL). Eight hours after LPS injection, rats received for an additional 10 h, at a same Fio2 (85%), either 15 parts per million NO or the same gas flow of nitrogen. We found that 18 h after LPS, lung wet, dry, and wet-to-dry weights, H2O2 production, and CD11b/CD18 expression were increased. PMN obtained from BAL were highly activated as evidenced by an already maximal expression of the beta2 integrin CD11b/CD18, whereas the high H2O2 production at basal state could be further enhanced after ex vivo stimulation. Blood PMN were not different from control cells at basal state; however, their increased capacity to be stimulated ex vivo suggested an in vivo priming effect of intratracheal LPS. In conclusion, inhaled NO, given with a high FiO2, in the presence of this established endotoxinic lung injury did not reverse the markers of PMN activation studied nor lung edema formation in this rat model.

The role of phagocytes in HIV-related oxidative stress.

BACKGROUND: in response to a variety of stimuli, phagocytes release large quantities of reactive oxygen species (ROS), which are essential for bacterial killing. However, excessive ROS production not appropriately compensated by antioxidant molecules can lead to oxidative stress, which may also play an important role in pathogenesis of HIV infection. In fact, ROS participate in chronic inflammation, HIV replication and the apoptosis of cells of the immune system. OBJECTIVE AND STUDY DESIGN: we used flow cytometry to study, in whole blood, the activation and redox status of polymorphonuclear neutrophils (PMN) and monocytes at different stages of the disease. RESULTS: we showed that neutrophils and monocytes from HIV-infected patients spontaneously produced increased amounts of H2O2. This increased H2O2 production was associated with alterations of adhesion molecules expression at the cell surface, which also reflected basal activation of phagocytes from the HIV-infected patients. In monocytes, basal H2O2 production correlated with viral load. This increased ROS production was associated with changes in the expression of the antiapoptotic/antioxidant compounds Bcl-2 and thioredoxin along the course of the disease. This modulation could result from a dual regulation by oxidative stress and could explain at least in part why monocyte numbers remain relatively stable throughout the disease. Monocytes expressed a normal maximal capacity to produce ROS in optimal conditions of stimulation. In contrast, after ex vivo priming with TNFalpha or IL-8, neutrophils showed a decreased H2O2 production in response to bacterial N-formyl peptides. This latter impairment correlated with the decrease in CD4+ lymphocyte numbers and with IL-8 and IL-6 plasma levels. CONCLUSIONS: the increased basal ROS production by phagocytes could participate to the oxidative injury which has been implicated in the pathophysiology of HIV infection. In addition, the decreased priming of H2O2 production by neutrophils could contribute to the increased susceptibility of HIV-infected patients to bacterial infections.

Genetic differences in response to pulmonary cytochrome P-450 inducers and oxygen toxicity.

The effects of cytochrome P-450 inducers on O2 toxicity were studied in mice. We first examined three cytochrome P-450 inducers, which differ by their specific tissue affinity: phenobarbital sodium (PB), essentially active in the liver, and 3-methylcholanthrene (3-MC) and beta-naphthoflavone (BNF), which are also active in the lung. Both BNF and 3-MC increased the survival rate and significantly decreased pulmonary edema (pulmonary water and wet-to-dry weight ratio) in C57BL/6J mice exposed to hyperoxia (O2 greater than or equal to 95%), whereas PB had no protective effect. In the second part of this study, we compared the action of BNF in two strains of mice. In one (C57BL/6J), cytochrome P-450 can be induced by aromatic hydrocarbons, whereas in the other (DBA/2J) cytochrome P-450 is not inducible by these compounds. Protection against O2 toxicity was assessed in terms of lethality and pulmonary edema and of lung lipid peroxidation (assessed by measuring malondialdehyde). BNF only protected against O2 toxicity in the inducible strain. This protective effect of BNF on O2 toxicity in C57BL/6J mice was associated mainly with a large increase in the components of the cytochrome P-450 system (cytochrome P-450 and cytochrome b5) in the lung. The activity of pulmonary superoxide dismutase was also slightly increased, but the enhancement was not statistically significant. In contrast, in DBA/2J mice neither the components of the cytochrome P-450 system nor the activity of superoxide dismutase showed any increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Absence of involvement of nitric oxide in LP-BM5-induced immunodeficiency syndrome.

To examine the role of nitric oxide (NO) in murine AIDS (MAIDS) pathogenesis, we determined NO production and inducible NOS (iNOS) mRNA expression in the macrophages of LP-BM5-infected mice, together with the in vivo effects of L-NAME, a competitive inhibitor of NO synthase. LP-BM5 infection induced neither spontaneous nitrite production nor iNOS mRNA expression. No differences in IFN gamma + LPS-induced nitrite production or iNOS mRNA expression were observed in macrophages, from non-infected or infected mice. Spleen weight, ecotropic MuLV replication, the blood lymphocyte phenotype and proliferative response of splenocytes were not modified by L-NAME. LP-BM5 infection did not increase macrophage NO production and NO production did not appear to protect against LP-BM5-induced immunodeficiency.