Search PubMed⌕ Search

Biomedical subjects

X Shi

Publications and source records attributed to X Shi.

At least 127 records · Page 7Linked to original sources
PubMed2000

Activation of mitogen-activated protein kinase p38 and extracellular signal-regulated kinase is involved in glass fiber-induced tumor necrosis factor-alpha production in macrophages.

In a previous study, we demonstrated that the length of glass fibers was a critical determinant of fiber potency in induction of tumor necrosis factor (TNF)-alpha and that activation of NF-kappaB was an important factor in this response. In the present study, we analyzed the role of mitogen-activated protein (MAP) kinases in the induction of TNF-alpha by glass fibers. Glass fibers induced phosphorylation of MAP kinases, p38, and ERK in primary rat alveolar macrophages, and this phosphorylation was associated with TNF-alpha gene expression. Long fibers were more potent than short fibers in activation of MAP kinases. Results from mechanistic analysis support that MAP kinases activate transcription factor c-Jun. The activated c-Jun acts on the TNF-alpha gene promoter through two binding sites, the cyclic AMP response element and the activator protein 1-binding site. These results suggest that in addition to the NF-kappaB pathway for TNF-alpha production, glass fibers are able to activate c-Jun through MAP kinase pathways that lead to induction of TNF-alpha expression.

Animals↗
PubMed2000

Zidovudine-didanosine coexposure potentiates DNA incorporation of zidovudine and mutagenesis in human cells.

Drug combinations that include nucleoside reverse transcriptase inhibitors (NRTIs) are remarkably effective in preventing maternal-viral transmission of HIV during pregnancy. However, there may be potential long-term risks for children exposed in utero. Examination of the genotoxic and mutagenic effects of two NRTIs, zidovudine [AZT (3'-azido-3'-deoxythymidine)] and didanosine [ddI (2',3'-dideoxyinosine)], in cultured human lymphoblastoid cells revealed multiplicative synergistic enhancement of AZT-DNA incorporation and mutant frequency induction in response to the combined drug exposure, as compared with single-drug exposures. Dose-related increases in DNA incorporation of AZT (as measured by a competitive RIA) and mutagenicity at the HPRT and TK loci (as assessed by cell-cloning assays) were observed in cells exposed in culture to AZT, or equimolar combinations of AZT + ddI, at exposure concentrations ranging from 3 to 30 times the maximum plasma levels found in humans. Because mutagenesis is strongly associated with tumor induction in experimental models, children exposed transplacentally to combinations of NRTIs may be at risk for cancer development later in life.

Anti-HIV Agents↗
PubMed2000

Vanadate induces p53 transactivation through hydrogen peroxide and causes apoptosis.

Vanadium is a metal widely distributed in the environment. Although vanadate-containing compounds exert potent toxic effects on a wide variety of biological systems, the mechanisms controlling vanadate-induced adverse effects remain to be elucidated. The present study investigated the vanadate-induced p53 activation and involvement of reactive oxygen species (ROS) in p53 activation as well as the role of p53 in apoptosis induction by vanadate. Exposure of mouse epidermal JB6 cells to vanadate led to transactivation of p53 activity in a time- and dose-dependent manner. It also caused mitochondrial damage, apoptosis, and generated ROS. Scavenging of vanadate-induced H(2)O(2) by N-acetyl-l-cysteine (a general antioxidant) or catalase (a specific H(2)O(2) inhibitor), or the chelation of vanadate by deferoxamine, resulted in inhibition of p53 activation and cell mitochondrial damage. In contract, an increase in H(2)O(2) generation in response to superoxide dismutase or NADPH enhanced these effects caused by vanadate. Furthermore, vanadate-induced apoptosis occurred in cells expressing wild-type p53 (p53+/+) but was very weak in p53-deficient (p53-/-) cells. These results demonstrate that vanadate induces p53 activation mainly through H(2)O(2) generation, and this activation is required for vanadate-induced apoptosis.

Acetylcysteine↗
PubMed2000

A novel casein kinase 2 alpha-subunit regulates membrane protein traffic in the human hepatoma cell line HuH-7.

A previously isolated endocytic trafficking mutant (TRF1) isolated from HuH-7 cells is defective in the distribution of subpopulations of cell-surface receptors for asialoorosomucoid (asialoglycoprotein receptor (ASGR)), transferrin, and mannose-terminating glycoproteins. The pleiotropic phenotype of TRF1 also includes an increased sensitivity to Pseudomonas toxin and deficient assembly and function of gap junctions. HuH-7xTRF1 hybrids exhibited a normal subcellular distribution of ASGR, consistent with the TRF1 mutation being recessive. A cDNA expression library derived from HuH-7 mRNA was transfected into TRF1 cells, which were subsequently selected for resistance to Pseudomonas toxin. Sequence analysis of a recovered cDNA revealed a unique isoform of casein kinase 2 (CK2), CK2alpha". Western blot analysis of TRF1 proteins revealed a 60% reduction in total CK2alpha expression. Consistent with this finding, the hybrids HuH-7xHuH-7 and HuH-7xTRF1 expressed equivalent amounts of total CK2alpha. Immunoblots using antibodies against peptides unique to the previously described CK2 isoforms CK2alpha and CK2alpha' and the novel CK2alpha" isoform showed that, although TRF1 and parental HuH-7 cells expressed comparable amounts of CK2alpha and CK2alpha', the mutant did not express CK2alpha". Based on the genomic DNA sequence, RNA transcripts encoding CK2alpha" apparently originate from alternative splicing of a primary transcript. Protein overexpression following transfection of TRF1 cells with cDNAs encoding either CK2alpha or the newly cloned CK2alpha" restored the parental HuH-7 phenotype, including Pseudomonas toxin resistance, cell-surface ASGR binding activity, phosphorylation, and the assembly of gap junctions. This study suggests that HuH-7 cells express at least three CK2alpha isoforms and that the pleiotropic TRF1 phenotype is a consequence of a reduction in total CK2 expression.

Amino Acid Sequence↗
PubMed2000

High-efficiency gene transfection of macrophages by lipoplexes.

Macrophage transfection studies are crucial for understanding gene regulation and expression. However, gene transfection in macrophages is difficult. We have shown here that macrophages are more resistant to gene transfection compared with other cell types. To further develop an efficient gene delivery system for macrophages, we evaluated various liposomal and non-liposomal agents including LipofectAMINE(R), Lipofectin(R), DOTAP, DEAE-dextran, and the DNA condensing agent protamine sulfate for their ability to promote gene transfection. CMV-luciferase was used as a reporter plasmid. Macrophage transfection was maximal at the DNA:LipofectAMINE:protamine ratio of 1:12:1 microg/ml. The LipofectAMINE formulation showed a 10-12-fold increase in transfection efficiency over DOTAP and a 4-5-fold increase over Lipofectin. This transfection method showed minimal toxicity at the concentrations tested and was at least 20-25-fold superior to the most frequently used DEAE-dextran method for macrophage transfection.

Animals↗
PubMed2000

Wood smoke particles generate free radicals and cause lipid peroxidation, DNA damage, NFkappaB activation and TNF-alpha release in macrophages.

The present study investigated the generation of free radicals by wood smoke and cellular injuries caused by these radicals. Wood smoke was collected after thermolysis of western bark. Electron spin resonance (ESR) techniques were used to measure both carbon-centered radicals and generation of reactive oxygen species (ROS) by wood smoke. Wood smoke, in the presence of H(2)O(2), was found to be able to generate hydroxyl radical (.OH). DNA strand breakage was measured by exposing wood smoke to lambda Hind III fragments using gel electrophoresis. Wood smoke combined with H(2)O(2) caused DNA damage. Sodium formate, an .OH radical scavenger, or deferoxamine, a metal chelator, inhibited the DNA damage. Cellular DNA damage was also measured in cultured RAW 264.7 mouse macrophage cells by the single cell gel (SCG) electrophoresis assay. Cells were exposed to wood smoke samples for various times and significant DNA damage was observed. Elemental analysis was performed on the filter samples and the presence of Fe was noteworthy. Wood smoke is also able to cause lipid peroxidation, activate nuclear transcription factor, NFkappaB, and enhance the release of TNF-alpha from RAW 264. 7 cells. The results indicate that the free radicals generated by wood smoke through the reaction of Fe with H(2)O(2) are able to cause DNA and cellular damage and may act as a fibrogenic agent.

Animals↗
PubMed2000

Heterotrophic production of biomass and lutein by Chlorella protothecoides on various nitrogen sources.

The effects of nitrate, ammonium, and urea as nitrogen sources on the heterotrophic growth of Chlorella protothecoides were investigated using flask cultures. No appreciable inhibitory effect on the algal growth was observed over a nitrogen concentration range of 0.85-1.7 g l(-)(1). In contrast, differences in specific growth rate and biomass production were found among the cultures with the various nitrogen compounds. The influence of different nitrogen sources at a concentration equivalent to 1.7 g l(-)(1) nitrogen on the heterotrophic production of biomass and lutein by C. protothecoides was investigated using the culture medium containing 40 g l(-)(1) glucose as the sole carbon and energy source in fermentors. The maximum biomass concentrations in the three cultures with nitrate, ammonium, and urea were 18.4, 18.9, and 19.6 g l(-)(1) dry cells, respectively. The maximum lutein yields in these cultures were between 68.42 and 83.81 mg l(-)(1). The highest yields of both biomass and lutein were achieved in the culture with urea. It was therefore concluded that urea was the best nitrogen source for the production of biomass and lutein. Based on the experimental results, a group of kinetic models describing cell growth, lutein production, and glucose and nitrogen consumption were proposed and a satisfactory fit was found between the experimental results and predicted values. Dynamic analysis of models demonstrated that enhancing initial nitrogen concentration in fermentor cultures, which correspondingly enhances cell growth and lutein formation, may shorten the fermentation cycle by 25-46%.

Journal Article↗
PubMed2000

3-Cyclobutenyl-1,2-dione-substituted porphyrins. A general and efficient entry to porphyrin-quinone and quinone-porphyrin-quinone architectures.

A new and efficient synthesis of meso-linked porphyrin-quinone dyads and quinone-porphyrin-quinone triads has been developed via the intermediacy of porphyrins bearing 3-cyclobutenyl-1,2-dione and 3-(1-ethenyl)cyclobutenyl-1,2-dione substituents at one or two nonadjacent meso-positions. The free-base porphyrins 5-bromo-10,20-diphenylporphyrin and 5,15-dibromo-10,20-diphenylporphyrin undergo facile palladium-catalyzed Stille coupling with 3-isopropoxy-2-tri-n-butylstannyl-cyclobutene-1,2-dione to produce the corresponding mono- and bis(3-cyclobutenyl-1,2-dione)-substituted porphyrins in good yields. In contrast, the zinc bromoporphyrins reacted with the same tin reagent only slowly and with the formation of side products. The free-base bromoporphyrins also were coupled with tri-n-butylvinyltin to afford vinylporphyrins in very good yields. 5,15-Diphenyl-10-vinylporphyrin was converted into trans-bromovinylporphyrin, which underwent facile Stille coupling with 3-isopropoxy-2-tri-n-butylstannylcyclobutene-1,2-dione to afford the vinylogous 3-cyclobutenyl-1,2-dione-substituted porphyrin. The molecular structure of 5,15-bis(3-cyclobutenyl-1,2-dione)-10,20-diphenylporphyrin(Z n) was determined by X-ray crystallography. Although the data revealed a fairly large dihedral angle between the cyclobutenedione and the porphyrin rings (57 degrees), the UV-vis spectra of both the mono- and bis(3-cyclobutenyl-1,2-dione)-substituted porphyrins showed B- and Q-band red shifts indicative of strong electronic coupling between the porphyrin and cyclobutenedione chromophores in solution. Introduction of a double bond between the cyclobutenedione and porphyrin rings resulted in a significant red shift of both the B- and Q-bands compared to those of the nonvinylogous system. All porphyrinic cyclobutenediones were metalated with zinc and then, using established cyclobutenedione chemistry, converted into a variety of porphyrin-quinones in excellent yields with aryllithium and vinylic Grignard reagents. From the mono(3-cyclobutenyl-1,2-dione)-substituted porphyrin, 7, a variety of directly linked monoquinone-porphyrin dyads were easily synthesized. Substituents could also be introduced at the free meso-position of 7 by bromination followed by palladium-catalyzed cross-coupling reactions, and additional porphyrinic monoquinones were then prepared from these starting materials. The vinylogous squarylporphyrin was converted into a double bond linked porphyrin-quinone via reaction with phenyllithium followed by thermal rearrangement and oxidation. As a result of the hindered rotation around the C-C bond between the porphyrin and the quinone, pairs of stable, separable, and thermally interconvertable atropisomers of porphyrin-quinones were obtained from 5,15-bis(3-cyclobutenyl-1,2-dione)-10,20-diphenylporphyrin(Z n). The structure of one of the atropisomers was determined by X-ray crystallography.

Crystallography, X-Ray↗
PubMed2000

3-Cyclobutenyl-1,2-dione-substituted porphyrins. 2. A simple and general entry to quinone-porphyrin-porphyrin-quinone tetrads and related molecules.

The synthesis of meso-linked quinone-porphyrin-porphyrin-quinone tetrads has been accomplished by the simple treatment of a CH2Cl2 solution of zincated 5-substituted-10,20-diphenylporphyrins (where the substituent = 3-cyclobutenyl-1,2-dione, various quinonyl derivatives, and p-anisyl) with 2,3-dichloro-5,6-dicyanoquinone (DDQ). The zincated porphyrinic quinones were synthesized from 5-(3-cyclobutenyl-1,2-dione)-10,20-diphenylporphyrin(Zn). The meso-linked dimer of 5-(3-cyclobutenyl-1,2-dione)-10,20-diphenylporphyrin(Zn) was also shown to be a useful precursor to meso-linked quinone-porphyrin-porphyrin-quinone tetrads. This DDQ-based oxidative dimerization appears to be general and effective for various zincated 5-substituted-10,20-diphenylporphyrins bearing both electron-withdrawing and -donating substituents. The oxidative dimerization was very sensitive to the reaction solvent (dimerization occurred in CH2Cl2, not in THF) and required the zincated porphyrins (the corresponding free base porphyrins did not undergo dimerization). When this solvent effect was applied to the reaction of I2/AgO2CCF3 with zincated porphyrins, either the dimeric porphyrins or iodoporphyrins could be selectively prepared simply by selecting methylene chloride or THF as the reaction solvent, respectively.

Cyclobutanes↗
PubMed2000

Smad6 as a transcriptional corepressor.

Smad6 and Smad7, a subgroup of Smad proteins, antagonize the signals elicited by transforming growth factor-beta. These two Smads, induced by transforming growth factor-beta or bone morphogenetic protein (BMP) stimulation, form stable associations with their activated type I receptors, blocking phosphorylation of receptor-regulated Smads in the cytoplasm. Here we show that Smad6 interacts with homeobox (Hox) c-8 as a transcriptional corepressor, inhibiting BMP signaling in the nucleus. The interaction between Smad6 and Hoxc-8 was identified by a yeast two-hybrid approach and further demonstrated by co-immunoprecipitation assays in cells. Gel shift assays show that Smad6, but not Smad7, interacts with both Hoxc-8 and Hoxa-9 as a heterodimer when binding to DNA. More importantly, the Smad6-Hoxc-8 complex inhibits interaction of Smad1 with Hoxc-8- and Smad1-induced transcription activity. These data indicate that Smad6 interacts with Hox transcription factors as part of the negative feedback circuit in the BMP signaling pathway.

Bone Morphogenetic Proteins↗
PubMed2000

Smad1 domains interacting with Hoxc-8 induce osteoblast differentiation.

Bone morphogenetic proteins are potent osteotropic agents that induce osteoblast differentiation and bone formation. The signal transduction of bone morphogenetic proteins has recently been discovered to involve Smad proteins. Smad1 is an essential intracellular component that is specifically phosphorylated by bone morphogenetic protein receptors and translocated into the nucleus upon ligand stimulation. Previously, we have reported that Smad1 activates osteopontin gene expression in response to bone morphogenetic protein simulation through an interaction with a homeodomain transcription factor, Hoxc-8. In the present study, the interaction domains between the two proteins were characterized by deletional analysis in both yeast two-hybrid and gel shift assays. Two regions within the amino-terminal 87 amino acid residues of Smad1 were mapped to interact with Hoxc-8, one of which binds to the homeodomain. Overexpression of recombinant cDNAs encoding the Hoxc-8 interaction domains of Smad1 effectively activated osteopontin gene transcription in transient transfection assays. Furthermore, stable expression of these Smad1 fragments in 2T3 osteoblast precursor cells stimulated osteoblast differentiation-related gene expression and led to mineralized bone matrix formation. Our data suggest that the interaction of amino-terminal Smad1 with Hoxc-8 mimics bone morphogenetic protein signaling and is sufficient to induce osteoblast differentiation and bone cell formation.

Alkaline Phosphatase↗
PubMed2000

Fructose-1,6-diphosphate and a glucose-free solution enhances functional recovery in hypothermic heart preservation.

BACKGROUND: Fructose-1,6-diphosphate (FDP) has been shown to protect tissue during hypoxia under various ischemic conditions, including isolated heart perfusion. We tested the hypothesis that adding FDP to St. Thomas solution can extend hypothermic heart preservation time. METHODS: Sixteen adult Sprague-Dawley rats were used. Under general anesthesia, the hearts were removed and preserved at 4 degrees C in St. Thomas solution (30 ml/kg) for 12 hours. FDP (5 mM) was added to the St. Thomas solution in the study group (n = 8), whereas no FDP was used in the control group (n = 10). The hearts were reperfused after 12 hours of preservation using a working heart model. RESULTS: In the study group, cardiac output ranged from 13.00 +/- 2.34 to 17.66 +/- 1.71 ml/min, maximum aortic flow was 3.40 +/- 1.99 to 9.26 +/- 1.72 ml/min, left ventricular stroke volume ranged from 0.074 +/- 0.014 to 0.092 +/- 0.009 ml, left ventricular stroke work ranged from 6.22 +/- 0.39 to 7.95 +/- 0.44 ml/mmHg, and maximum left ventricular generated power was 14.38 +/- 2.94 to 20.16 +/- 2.49 Joules/min. All of these parameters were higher than those in the control group (p < 0.001). Coronary vascular resistance and myocardial tissue wet/dry weight ratio were lower in the study group than in the control group (p < 0.05). CONCLUSIONS: Heart function was better preserved when FDP was added to St. Thomas solution during hypothermic rat heart preservation. The mechanism is not totally clear, but enhancement of high-energy phosphate production during ischemia is possible. Key words: heart, procurement, hypothermia, fructose-1,6-diphosphate.

Animals↗
PubMed2000

Activation of AP-1 through the MAP kinase pathway: a potential mechanism of the carcinogenic effect of arenediazonium ions.

Arenediazonium ions such as those found in the common mushroom Agaricus bisporus have been convincingly demonstrated to be tumorigenic. The specific mechanism of their tumorigenicity remains unclear. It has been shown that arenediazonium ions can be metabolized to aryl radicals, and that reaction of these aryl radicals with DNA produces aryl adducts. These metabolic processes also produce the reactive oxygen species superoxide and hydroxyl radicals which have been implicated in AP-1 activation. To further investigate the mechanism of tumorigenesis by arenediazonium ions, we studied the effect of a representative arenediazonium ion on AP-1 activation and phosphorylation of the signal transduction proteins ERK1, ERK2, JNK, and p38 kinase, both in vitro and in vivo. We also identified the specific radicals produced by spin trapping and ESR analysis. Here, it was found that p-methylbenzenediazonium ion (2a) induced a 16-fold increase in the extent of AP-1 activation at micromolar concentrations, and that this increase coincided with phosphorylation of the signaling kinases ERK1 and -2 and p38 kinase, but not JNK, in JB6 mouse epithelial cells. In vivo studies using AP-1 luciferase reporter-bearing transgenic mice supported the increase in the extent of AP-1 activation in 2a-treated mice over controls, and showed that this effect was different in different tissue types. The antioxidant N-acetylcysteine (NAC), a general antioxidant, showed an inhibitory effect on 2a-mediated AP-1 induction, while aspirin, a hydroxyl radical scavenger, had no effect. Spin trapping studies showed that while NAC suppressed radical formation from 2a, aspirin did not alter radical production from 2a. It appears that 3a, a carbon-centered radical formed from 2a, is responsible for AP-1-induced activation, and therefore, radical species that are not oxygen-centered are also capable of inducing AP-1. These results represent a step toward understanding the mechanism of tumorigenicity of arenediazonium ions.

Acetylcysteine↗
PubMed2000

UVA-Induced DNA single-strand cleavage by 1-hydroxypyrene and formation of covalent adducts between DNA and 1-hydroxypyrene.

1-Hydroxypyrene (HOP), a metabolite found in the urine of humans and laboratory animals exposed to polycyclic aromatic hydrocarbons (PAHs), is known to be both acutely toxic and genotoxic. It has been widely used as a biomarker for studying PAH exposure. In this research, we have found that, upon UVA irradiation, HOP causes DNA single-strand cleavages and forms HOP-DNA covalent adducts. The UVA-induced cleavage of supercoiled plasmid PhiX174 DNA is dependent upon both HOP concentration and UVA dosage. A longer irradiation time or higher HOP concentration induces more DNA cleavage. Results of the photocleavage experiments carried out in the presence of reactive oxygen species scavengers, histidine, sodium azide, mannitol, SOD, and desferal indicate that both the superoxide free radical and singlet oxygen are likely involved in causing DNA single-strand cleavage. The photocleavage is inhibited by the presence of an excited singlet-state quencher, KI, indicating that it is an excited-state reaction. Along with light-induced DNA cleavage, HOP also forms DNA covalent adducts while being degraded upon light irradiation. Light-induced degradation of 20 microM HOP follows first-order reaction kinetics in a 10% methanolic buffer (10 mM phosphate) solution in the absence or presence of 40 microM calf thymus DNA, with degradation half-lives of 20 or 15 min, respectively. The shorter degradation half-life in the presence of DNA is due to the formation of the HOP-DNA covalent adduct. The formation of the HOP-DNA covalent adduct is evidenced by comparing the UV-vis absorption and fluorescence emission spectra of the pure HOP with those of the HOP-DNA adduct. The covalent HOP-DNA adduct produced due to irradiation was purified by either extensive dialysis (3 x 500 mL buffer solutions), phenol and chloroform extraction followed by ethanol precipitation, or chloroform extraction alone. The isolated HOP-DNA adduct has an absorption peak at 353 nm, which is 8 nm red-shifted compared to that of free HOP. The fluorescence emission for HOP-DNA is at least 70 times weaker than that for free HOP in solution. In summary, the findings with HOP reveal that, in addition to metabolic activation that eventually leads to the formation of alkylated DNA adducts or other forms of DNA damage, HOP may be activated by light to produce DNA single-strand cleavage and covalent DNA adducts. These DNA lesions can be sources of toxicity.

Animals↗
PubMed2000

Antioxidant properties of (-)-epicatechin-3-gallate and its inhibition of Cr(VI)-induced DNA damage and Cr(IV)- or TPA-stimulated NF-kappaB activation.

Electron spin resonance (ESR) spin trapping was utilized to investigate the scavenging effects on hydroxyl radicals (*OH) and superoxide radicals (O2*-) by (-)-epigallocatechin-3-gallate (EGCG), one of the major anticancer compounds in tea. The spin trap used was 5,5-dimethyl-pyrroline N-oxide (DMPO). The Fenton reaction (Fe2+ + H2O2-->Fe3+ + *OH + OH-) was used as a source of *OH radicals. EGCG efficiently scavenges *OH radicals with reaction rate of 4.62 x 10(11) M(-1)sec(-1), which is an order of magnitude higher than several well recognized antioxidants, such as ascorbate, glutathione and cysteine. It also scavenges O2*- radicals as demonstrated by using xanthine and xanthine oxidase system as a source of O2*- radicals. Through its antioxidant properties, EGCG exhibited a protective effect against DNA damage induced by Cr(VI). EGCG also inhibited activation of nuclear transcription factor NF-kappaB induced by Cr(IV) and 12-o-tetradecanoylphorbol-13-acetate (TPA). The present studies provide a mechanistic basis for the reported anticarcinogenic properties of EGCG and related tea products.

Antioxidants↗
PubMed2000

Oxygen radical-mediated pulmonary toxicity induced by some cationic liposomes.

PURPOSE: The objectives of this study are to investigate the toxicity associated with polycationic liposomes and to elucidate the underlying mechanism. We tested the hypothesis that the positive charge of liposomes is a key determinant of toxicity by testing differently charged liposomes in mice. METHODS: Differently charged liposomal systems including cationic liposomes, LipofectAMINE and DOTAP, and neutral and negative liposomes were evaluated for their toxicity after pulmonary administration in mice. LDH assay and differential cell counts were performed to measure toxicity and pulmonary inflammation, respectively. Reactive oxygen intermediates (ROI) were assessed by chemiluminescence. RESULTS: Instillation of cationic liposomes elicited dose-dependent toxicity and pulmonary inflammation. This effect was more pronounced with the multivalent cationic liposome LipofectAMINE as compared to the monovalent cationic DOTAP. Neutral and negative liposomes did not exhibit lung toxicity. Toxicity associated with cationic liposomes correlated with the oxidative burst induced by the liposomes. LipofectAMINE induced a dose-dependent increase in ROI generation. This effect was less pronounced with DOTAP and absent with neutral and negative liposomes. CONCLUSIONS: ROI play a key role in cationic lipid-mediated toxicity. Polyvalent cationic liposomes cause a release of ROI which are responsible for the pulmonary toxicity.

Animals↗