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Biomedical subjects

Z Xing

Publications and source records attributed to Z Xing.

At least 91 records · Page 5Linked to original sources
PubMed1995

[Manufacture of computer-based testing and analyzing system for measuring step-through performance].

The computer-Based Testing and Analysing System for measuring Step-Through (avoiding darkness) performance (CTASS) has been developed. The system is based on the infrared beams which transfer actions of mice inside the boxes into signals of voltage. The signals are fed into the computer through A/D converter to computer for software processing. The functions which have been realized include, but not limited to: signal sampling and data curve displaying; intelligent identification and elimination of jamming signal; auto-calculation of number of errors (No) in all channels, latent period (LP) of entering into the light chamber, total time of mice staying in the light chamber (safty place Tl) and dark chamber (error place Td); hardcopy of screen graphics and resulting output by various printers. The CATSS system was applied to test normal mice and the cognition-deficient mice induced by anisodine, a M-Cholinergic antagonist at a dose of 1-10 mg/kg i.p. The data collected by the system were compared and proved to be consistent with those acquired by manual labour. The system has produced refined and accurate information refined to a maximum extent and guaranteed scientifically sound experimental results. It is foreseable that introducing the computer into pharmacological researches will update and advance their methodology.

Animals↗
PubMed1994

Adenovirus-mediated cytokine gene transfer at tissue sites. Overexpression of IL-6 induces lymphocytic hyperplasia in the lung.

The biologic function of cytokines may be best studied in the context of a defined tissue site. To establish a model for studying the function of IL-6 at local tissue sites, we targeted the IL-6 transgene into the bronchial epithelium in the lung of Sprague-Dawley rats by intratracheal administration of a recombinant human type 5 adenovirus with rat IL-6 cDNA incorporated into the E3 region of the viral genome. This approach led to a highly compartmentalized overexpression of the IL-6 transgene and production of bioactive protein within the lung for about 7 days post-infection. Associated with this overexpression of IL-6 was the development of profound local lymphocytic hyperplasia around day 7, characterized by the dramatic expansion of bronchial associated lymphoid aggregates and massive lymphocytic infiltration in the pulmonary parenchyma. Concurrently, there were strikingly increased numbers of lymphocytes in bronchoalveolar lavage fluids. The majority of these lymphocytes were found to be CD3+CD8+ cytotoxic T and CD3+CD4+ helper T cells with the remaining being primarily a small number of CD45R+ B cells. In addition, there was moderate bronchial and alveolar epithelial hyperplasia associated with lymphocytic hyperplasia. However, all of these changes subsided concomitant with the decrease in IL-6 expression and the lung seemed normal at 12 to 14 days post-infection. Thus, our study provides a tissue-specific transient transgene model for investigating cytokine functions in vivo and demonstrates that IL-6 has a profound stimulatory effect on the local lymphoid tissue in the lung.

Adenoviruses, Human↗
PubMed1994

Interleukin 10 inhibits lipopolysaccharide-induced survival and cytokine production by human peripheral blood eosinophils.

In this study we have investigated the effects of interleukin 10 (IL-10) on human peripheral blood eosinophils stimulated with granulocyte/macrophage colony stimulating factor (GM-CSF) and lipopolysaccharide (LPS). We show that LPS was able to enhance eosinophil survival in a dose-dependent manner, as well as release of the cytokines GM-CSF, tumor necrosis factor alpha, and IL-8. LPS-induced eosinophil survival was largely inhibited by an anti-GM-CSF neutralizing antibody and completely blocked by polymyxin B, suggesting GM-CSF involvement in the survival enhancing mechanism and LPS specificity, respectively. IL-10 significantly inhibited survival of, and cytokine production from, eosinophils induced by LPS, but did not inhibit the survival induced by GM-CSF. These observations suggest a novel activation mechanism of eosinophils and, also, that IL-10 may participate in the regulation of diseases characterized by eosinophil infiltration.

Antibodies↗
PubMed1994

A role for CD4+ T cells in the pathogenesis of skin fibrosis in tight skin mice.

The tight skin (Tsk/+) mouse represents a murine model of heritable fibrosis with some similarities to the skin fibrosis seen in human scleroderma. Tsk/+ animals display alterations in connective tissue in some internal organs. Skin fibrosis can be adoptively transferred to normal recipients with Tsk/+ bone marrow or spleen cells and older Tsk/+ animals develop autoantibodies against topoisomerase suggesting that some of the pathogenesis in the Tsk/+ mouse may be mediated by autoimmunity. To determine the role of T cell subsets in the pathogenesis of fibrotic disease, Tsk/+ mice were bred with CD4- and CD8-deficient (CD4-/- and CD8-/-) mice. Tsk/+ CD4-/- mice showed a marked reduction in skin fibrosis as well as decreased cellularity and only mild collagen disorganization as compared to Tsk/+ CD4+ CD8+ control mice yet did not differ from Tsk controls in the level of serum anti-topoisomerase activity. In contrast, Tsk/+ CD8-/- mice exhibited the same histology in the skin as Tsk/+ controls yet had significantly reduced levels of serum anti-topoisomerase activity. Lung pathology, i.e. emphysema, was unaffected by both the CD4 or CD8 mutations. These data show that only some of the pathological effects of the Tsk mutation are T cell dependent and that different T cell subsets affect different parameters in this multi-organ model of fibrotic disease.

Animals↗
PubMed1994

Direct interaction of v-Src with the focal adhesion kinase mediated by the Src SH2 domain.

The recently described focal adhesion kinase (FAK) has been implicated in signal transduction pathways initiated by cell adhesion receptor integrins and by neuropeptide growth factors. To examine the mechanisms by which FAK relays signals from the membrane to the cell interior, we carried out a series of experiments to detect potential FAK interactions with proteins containing Src homology 2 (SH2) domains that are important intracellular signaling molecules. Using v-Src-transformed NIH3T3 cells, we showed that FAK was present in the immune-complex precipitated by anti-Src antibody, suggesting potential interaction of FAK with v-Src in vivo. We also showed potentially direct interaction of FAK with v-Src in vivo using the yeast two-hybrid system. Using recombinant FAK expressed in insect cells and bacterial fusion proteins containing Src SH2 domains, we showed direct binding of FAK to the Src SH2 domain but not to the SH3 domain in vitro. A kinase-defective mutant of FAK, which is not autophosphorylated, did not interact with the Src SH2 domain under the same conditions, suggesting the involvement of the FAK autophosphorylation sites. Treatment of FAK with a protein-tyrosine phosphatase decreased its binding to the Src SH2 domain, whereas autophosphorylation in vitro increased its binding. These results confirm the importance of FAK autophosphorylation sites in its interaction with SH2 domain-containing proteins. Taken together, these results suggest that FAK may mediate signal transduction events initiated on the cell surface by kinase activation and autophosphorylation that result in its binding to other key intracellular signaling molecules.

3T3 Cells↗
PubMed1994

Cytokine expression by neutrophils and macrophages in vivo: endotoxin induces tumor necrosis factor-alpha, macrophage inflammatory protein-2, interleukin-1 beta, and interleukin-6 but not RANTES or transforming growth factor-beta 1 mRNA expression in acute lung inflammation.

Using a rat model of acute lung inflammation induced by intratracheal instillation of lipopolysaccharide (LPS), we investigated the kinetics of mRNA expression and the potential cellular sources of tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2), interleukin (IL)-1 beta, IL-6, RANTES, and transforming growth factor-beta 1 (TGF-beta 1). By Northern blot analysis, TNF-alpha and MIP-2 mRNAs in total lung tissue increased markedly by 30 min and peaked by 1 h after LPS exposure, whereas expression of IL-1 beta and IL-6 was not detected until 1 h and peaked within 6 h. In contrast, neither RANTES nor TGF-beta 1 mRNA was induced by LPS throughout 72 h, although a basal expression was detected in both saline- and LPS-treated lung tissues. At 1 h after LPS, the bronchoalveolar lavage (BAL) fluid contained about 98% alveolar macrophages (AM), whereas by 6 or 12 h, 88% of BAL cells were polymorphonuclear neutrophils (PMN). Upon extraction of total RNA after separation of AM from PMN in BAL, Northern analysis showed that at 1 h, AM expressed pronounced signals for TNF-alpha, MIP-2, IL-1 beta, and IL-6. At 6 and 12 h, however, while cytokine transcripts decreased in AM, PMN exhibited strong signals for these cytokines. A low basal noninducible signal for TGF-beta 1 but not RANTES was detected in both AM and PMN. Finally, by in situ hybridization techniques, PMN in the lung tissue, particularly those located in the vicinity of the bronchiole and vasculature, were demonstrated to localize MIP-2 mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

An anti-lymphocytic choriomeningitis virus ribozyme expressed in tissue culture cells diminishes viral RNA levels and leads to a reduction in infectious virus yield.

Ribozymes, RNA molecules which cleave RNA in a sequence-specific manner, are a promising tool in the development of specific antiviral therapies. The viruses most susceptible to ribozymes may be those in which all aspects of the viral life cycle depend on RNA, with no DNA intermediate. Consequently, we have chosen as a model one such virus, the arenavirus lymphocytic choriomeningitis virus (LCMV), and have previously reported the design of specific anti-LCMV ribozymes (Z. Xing and J. L. Whitton, J. Virol. 66:1361-1369, 1992). Here we describe the establishment of several cell lines, each stably expressing an antiarenaviral ribozyme of different specificity. Expression of a single ribozyme leads to a reduction in LCMV RNA levels, and stimulation of ribozyme transcription amplifies the effect. Target site selection may be an important determinant of antiviral effectiveness, since the extent of the antiviral effect, measured by assay of viral RNA, varies with the specificity of the antiviral ribozyme expressed. Furthermore, infectious virus production is reduced approximately 100-fold. This effect is LCMV specific, as yield of a related arenavirus is not similarly curtailed. We are currently investigating the mechanism underlying the ribozyme-mediated antiviral effect.

Animals↗
PubMed1993

Lipopolysaccharide induces expression of granulocyte/macrophage colony-stimulating factor, interleukin-8, and interleukin-6 in human nasal, but not lung, fibroblasts: evidence for heterogeneity within the respiratory tract.

Fibroblasts play an indirect augmenting effector role in the inflammatory response by releasing growth and differentiation factors and other inflammatory mediators after activation by inflammatory cytokines such as interleukin (IL)-1, but whether direct activation occurs by exogenous agents such as endotoxin (lipopolysaccharide, LPS) remains controversial. Using a number of primary human airways tissue-derived fibroblast lines, we demonstrate that in contrast to IL-1 alpha, LPS significantly induced gene expression and production of granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-8, and IL-6 only in nasal but not bronchial or lung tissue-derived fibroblasts. Enhanced expression was dose- and time-dependent, and the minimal stimulatory dose was 10 ng LPS/ml. Polymyxin B entirely abrogated increased cytokine expression by LPS. Actinomycin D treatment largely inhibited expression, and LPS markedly increased an IL-6 gene promoter-driven luciferase reporter response in transfected nasal fibroblasts, suggesting enhanced expression may involve transcriptional regulation. Secondary protein or IL-1 synthesis requirement seemed unlikely since cycloheximide superinduced LPS-stimulated cytokine expression and anti-IL-1 alpha/beta antibodies failed to abrogate the response. Thus our data show that GM-CSF, IL-8, and IL-6 are directly inducible in nasal fibroblasts by LPS, and establish heterogeneous responsiveness to LPS by different fibroblast populations in the airways.

Animals↗
PubMed1993

Polymorphonuclear leukocytes as a significant source of tumor necrosis factor-alpha in endotoxin-challenged lung tissue.

The kinetic expression and potential cellular source of tumor necrosis factor-alpha (TNF-alpha) in lipopolysaccharide-(LPS) induced acute lung inflammation was investigated using a rat model by Northern blot analysis, in situ hybridization and immunohistochemistry. LPS induced a polymorphonuclear leukocyte infiltrate in the lung that peaked between 6 and 24 hours. TNF-alpha messenger (m)RNA was strongly induced by LPS in whole lung tissues shown by Northern analysis. Both alveolar macrophages and polymorphonuclear leukocytes (PMNs), purified from bronchoalveolar lavage fluids of LPS-treated rats, were shown to express TNF-alpha mRNA by Northern analysis. However, PMNs displayed several times more TNF-alpha mRNA, relative to actin mRNA, than alveolar macrophages at 6 and 12 hours. By in situ hybridization, most of the cells positive for TNF-alpha mRNA at 6 and 12 hours seemed to be PMNs located within the tissue near bronchioles or vessels. By immunohistochemistry, TNF-alpha protein was localized mainly to alveolar macrophages at early times (1 to 3 hours) after LPS challenge, and thereafter, PMNs seemed to be the predominant source of TNF-alpha protein as more than 90% of total intraalveolar positive cells at 6 and 12 hours were PMN. Thus, our data provide the first in vivo evidence that PMNs can serve as a significant source of TNF-alpha at sites of acute inflammation.

Animals↗
PubMed1992

Intra-hepatic-arterial infusion of misonidazole--an experimental study of regional radiosensitisation by intraarterial embolisation.

The purpose of this study was to generate a selective radiosensitising effect by the intra-hepatic-arterial infusion of misonidazole (MISO). MISO (10 mg) was infused after transcatheter hepatic-arterial embolisation into the livers of rabbits bearing VX2 liver cancer. This procedure was followed by 15 Gy electron irradiation. Evaluation of tumour volume and histological examination was carried out on the 7th day after treatment. The greatest tumour response was obtained in the group which received MISO followed by radiation and was characterised by extensive fibrosis around the tumour and nearly complete tumour necrosis. Liver cell regeneration was also noted in adjacent liver tissue. The advantages of regional infusion of MISO following hepatic-arterial embolisation are: (1) Selectivity increased radiosensitivity of liver cancer alongside very low drug concentration in the plasma. (2) Reduced or absent deleterious side effects of MISO with higher tumour/normal tissue ratios of drug concentration. (3) Reduced cost due to the lower dosage of MISO required for regional infusion.

Animals↗
PubMed1992

Ribozymes which cleave arenavirus RNAs: identification of susceptible target sites and inhibition by target site secondary structure.

The development of safe and effective antiviral agents has been a slow process, largely because of the difficulty in distinguishing between virus and host functions; materials toxic to the virus are frequently harmful also to the host in which the agent resides. Recently, techniques which target nucleic acid sequences as a means of reducing gene expression have emerged. This antisense armamentarium includes ribozymes, RNA enzymes which cleave other RNA molecules in a sequence-specific manner. We wish to assess the ability of ribozymes to control animal virus infection. Reasoning that the viruses most vulnerable to ribozyme intervention will be those whose complete life cycle is based on RNA (with no DNA stage), we have begun to develop ribozymes directed toward lymphocytic choriomeningitis virus (LCMV), the prototype of the arenavirus family. Using ribozymes of the hammerhead variety, we have identified several sites on the LCMV genome which can be efficiently cleaved in trans. The efficiency of cleavage is site dependent, and we demonstrate that secondary structure at the target site can abolish ribozyme cleavage. Computer-assisted analysis indicates that much of the LCMV genome may be involved in base pairing, which may render it similarly resistant to ribozyme attack. The few remaining open regions of LCMV lack a GUC target site, on which most studies to date have relied. Here we show that AUC, CUC, and AUU are alternative sites which can be cleaved by trans-acting ribozymes. This finding is important given the aforementioned restriction of available sites, imposed by secondary structure.

Arenaviridae↗
PubMed1992

IL-1 beta and IL-6 gene expression in alveolar macrophages: modulation by extracellular matrices.

Interleukin-1 (IL-1) and interleukin-6 (IL-6) are two cytokines involved in a variety of host inflammatory reactions. The alveolar macrophage (AM), a predominant cell source for IL-1 and IL-6, exists in a microenvironment in which there are abundant extracellular matrix (ECM) components, and it is likely that ECM may participate in the inflammatory response in the lung by modulating the effector activities of AMs. To investigate this hypothesis, we cultured rat AMs on different substrates including plastic, collagen, and airways fibroblast-derived ECM (fECM) and assessed IL-1 beta and IL-6 gene expression in these cells. Our study demonstrates that cytokine gene expression in AMs is affected by the conditions of culture. IL-1 gene expression is stimulated by adherence to plastic and exposure to endotoxin, whereas IL-6 mRNA is detectable only in the cells stimulated by endotoxin. Coating the plastic with collagen or fECM modifies cytokine gene expression. At early time points, collagen enhances gene expression. At later times (5 days), actin and cytokine gene expression are predominantly maintained in the endotoxin-stimulated cells cultured on fECM. These findings suggest an extracellular environment-directed mechanism of regulation of cytokine expression in alveolar macrophages.

Actins↗
PubMed1992

Human upper airway structural cell-derived cytokines support human peripheral blood monocyte survival: a potential mechanism for monocyte/macrophage accumulation in the tissue.

A central feature of chronic airway inflammation is accumulation of monocyte/macrophages in the tissue. It is well known that circulating monocytes are short-lived cells whereas tissue macrophages are longer-lived cells. One mechanism that may account for accumulation of inflammatory cells includes enhanced survival and/or differentiation of these cells. Recent studies imply that signals released by tissue structural cells may be crucial in these events. To investigate this notion, human blood monocytes were cultured with either culture medium alone as a control, human nasal epithelial cell-conditioned medium (EpCM), or fibroblast-conditioned medium (FCM) for more than 1 wk. Survival of monocytes in medium alone was 17% at day 7, whereas survival of those cultured with 50% of EpCM or FCM was 62% and 64%, respectively. The effect of EpCM and FCM was dose dependent. Preincubation of either conditioned medium (CM) with an antibody against granulocyte/macrophage colony-stimulating factor (GM-CSF) or an antibody against macrophage colony-stimulating factor (M-CSF) resulted in a partial abrogation of the survival-enhancing effect, to an average of 50% and 30%, respectively. Complete inhibition was obtained by preincubation of the CM with a combination of both antibodies. The effect of CM represented true survival because CM only induced a low profile of [3H]thymidine incorporation and, furthermore, less than 0.3% of the cells cultured with CM underwent DNA synthesis as assessed by autoradiography. In addition, ultrastructural observations demonstrated that most monocytes cultured with either CM but not with control culture medium assumed ultrastructural features of macrophages by day 8 of culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Differentiation↗
PubMed1991

[The preparation of highly purified insulin and its clinical use. Insulin Cooperative Study Group].

Antigenicity of insulin preparations is obviously related to their purity. The average contents of proinsulin, glucagon and pancreatic polypeptide in highly purified insulin (HP-I) produced by us are 76.0, 2.11 and 0.11 ppm respectively. These results are superior to those for domestic conventional crystalline insulin and single peak insulin (SP-I). The antibodies to insulin, proinsulin and pancreatic polypeptide in serum were examined in 24 diabetic patients treated with HP-I for more than 6 months. The positive rates for the above three antibodies were 37.5%, 0% and 0% respectively. The results showed that the antigenicity of HP-I was much lower than that of domestic conventional crystalline insulin and almost the same as that of MC-I from Nordisk, Denmark.

Autoantibodies↗