Biomedical subjects

H Wang

Publications and source records attributed to H Wang.

At least 1,387 records · Page 77Linked to original sources

PubMed1998

Influence of adrenal glands on the modulation of prolactin gene expression by the endogenous benzodiazepine ligand octadecaneuropeptide in the male rat pituitary gland.

Recently, an 86-amino acid polypeptide with high affinity for diazepam binding sites, termed diazepam-binding inhibitor (DBI), has been found in the rat brain. DBI, as well as a peptide derived from DBI, the octadecaneuropeptide DBI[33-50] (ODN), interacts with the GABA(A) receptor complex. To investigate the role of these endogenous ligands for GABA(A) receptors on prolactin gene expression, we studied the effects of acute intracerebroventricular administration (4 h before sacrifice) of ODN on prolactin mRNA levels in the male rat. Because, in some neuropeptidergic systems, glucocorticoids play a role in the response to ODN, we also studied the influence of adrenal glands and the effect of dexamethasone administration in the response of prolactin gene expression to ODN. ODN injection produced an increase in prolactin mRNA levels. Adrenalectomy performed 5 days before sacrifice resulted in an increase in prolactin gene expression and also potentiated the stimulating effect of ODN. Because castration has been shown to decrease prolactin gene expression in the male rat, we used castrated and adrenalectomized animals to study the role of dexamethasone in the response of lactotrophs to ODN. In these steroid-deprived animals, dexamethasone treatment (for 4 days) decreased prolactin mRNA levels but did not modify the response to ODN. These data indicate that an endogenous neuropeptide interacting with the GABA(A) receptor complex can stimulate prolactin gene expression and suggest that the adrenal glands may produce factor(s) capable of decreasing prolactin mRNA. On the other hand, it does not appear that glucocorticoid hormones play a role in the effect of ODN on lactotroph activity.

Adrenal Glands↗

PubMed1998

ICK1, a cyclin-dependent protein kinase inhibitor from Arabidopsis thaliana interacts with both Cdc2a and CycD3, and its expression is induced by abscisic acid.

Cyclin-dependent kinase (CDK) inhibitor genes encode low molecular weight proteins which have important functions in cell cycle regulation, development and perhaps also in tumorigenesis. The first plant CDK inhibitor gene ICK1 was recently identified from Arabidopsis thaliana. Although the C-terminal domain of ICK1 contained an important consensus sequence with the mammalian CDK inhibitor p27Kip1, the remainder of the deduced ICK1 sequence showed little similarity to any known CDK inhibitors. In vitro assays showed that recombinant ICK1 exhibited unique kinase inhibitory properties. In the present study we characterized ICK1 in terms of its gene structure, its interaction with both A. thaliana Cdc2a and CycD3, and its induction by the plant growth regulator, abscisic acid (ABA). ICK1 was expressed at a relatively low level in the tissues surveyed. However, ICK1 was induced by ABA, and along with ICK1 induction there was a decrease in Cdc2-like histone H1 kinase activity. These results suggest a molecular mechanism by which plant cell division might be inhibited by ABA. ICK1 clones were also identified from independent yeast two-hybrid screens using the CycD3 construct. The implication that ICK1 protein could interact with both Cdc2a and CycD3 was confirmed by in vitro binding assays. Furthermore, deletion analysis indicated that different regions of ICK1 are required for the interactions with Cdc2a and CycD3. These results provide a mechanistic basis for understanding the role of CDK inhibitors in cell cycle regulation in plant cells.

Abscisic Acid↗

PubMed1998

Regulation of renal phosphate transport by acute and chronic metabolic acidosis in the rat.

Metabolic acidosis results in impaired renal tubular phosphate reabsorption and proximal tubular apical brush border membrane (BBM) sodium gradient-dependent phosphate transport (Na/Pi cotransport) activity. In the present study we investigated the cellular mechanisms responsible for decreased Na/Pi cotransport activity following six hours to 10 days of metabolic acidosis induced by ingestion of NH4Cl. Urinary Pi excretion was significantly increased and BBM Na/Pi cotransport activity was progressively and significantly decreased by 18% at six hours, 24% at 12 hours, 32% at 24 hours, and 61% after 10 days of metabolic acidosis. The progressive and time-dependent decreases in BBM cotransport activity were associated with progressive decreases in BBM NaPi-2 protein (43% at 12 hr, 54% at 24 hr and 66% at 10 days) and cortical NaPi-2 mRNA (22% at 12 hr, 54% at 24 hr and 56% at 10 days) abundance. Interestingly, following six hours of metabolic acidosis, there was a significant 29% decrease in BBM NaPi-2 protein abundance that was not associated with decreases in either cortical homogenate NaPi-2 protein or cortical NaPi-2 mRNA abundance. In additional studies we found that the effects of chronic metabolic acidosis on Na/Pi cotransport activity were independent of endogenous parathyroid hormone activity, but were somewhat dependent on dietary Pi intake. In rats fed a high or a normal Pi diet metabolic acidosis caused significant decreases in Na/Pi cotransport activity, NaPi-2 protein and NaPi-2 mRNA abundance, however, in rats fed a low Pi diet the inhibitory effect of metabolic acidosis on Na/Pi cotransport were minimal and not significant. These results indicate that in chronic (> or = 12 hr) metabolic acidosis the progressive decrease in BBM Na/Pi cotransport activity is most likely mediated by decrease in BBM NaPi-2 protein and cortical mRNA abundance. In contrast, in acute (< or = 6 hr) metabolic acidosis the decrease in BBM Na/Pi cotransport activity is likely mediated by changes in the trafficking of the NaPi-2 protein that is, enhanced internalization from and/or impaired delivery of the NaPi-2 protein to the apical BBM.

Acidosis↗

PubMed1998

Free radical scavenging activity of fermented papaya preparation and its effect on lipid peroxide level and superoxide dismutase activity in iron-induced epileptic foci of rats.

Fermented papaya preparation is a natural health food that has been commercially sold in Japan for 2 years. It is made by yeast fermentation of Carica Papaya Linn. We examined the antioxidant action of the fermented papaya preparation on free radicals and lipid peroxidation. Free radicals have been related with aging and diseases, such as cancer, diabetes and especially in neurological disorders, for example, Parkinson's disease or Alzheimer's disease. A diet including variable antioxidant foods may therefore help to prevent these illnesses. The free radical scavenging activity of the fermented papaya preparation was examined using an electron spin resonance (ESR) spectrometer. Fermented papaya preparation (50 mg/ml) scavenged 80% of hydroxyl radicals (.OH) as spin adducts of spin trap, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) (5.27 x 10(15)spins/ml) generated by Fenton reagents. The value of IC50 was 12.5 mg/ml. The oral administration of the fermented papaya preparation for 4 weeks decreased the elevated of lipid peroxide levels in the ipsilateral 30 min after injection of iron solution by iron into the left cortex of rats. The fermented papaya preparation also increased superoxide dismutase activity in the cortex and hippocampus of them. These results suggest that the fermented papaya preparation has antioxidant actions and that it may be prophylactic food against the age related and neurological diseases associated with free radicals.

Administration, Oral↗

PubMed1998

The use of a chimera HIV-1/HIV-2 envelope protein for immunodiagnosis of HIV infection: its expression and purification in E. coli by use of a translation initiation site within HIV-1 env gene.

A chimera HIV-1/HIV-2 envelope sequence composed of multiple conserved immunodominant epitopes of HIV-1 envelope protein (HIV-1 IIIB: env482-518 + env548-675) and the HIV-2 gp36 immunodominant epitope (env592-603), was constructed and directly over-expressed in E. coli by using a prokaryotic translation initiation sequence contained within the gene of HIV-1 envelope. The recombinant product was purified and applied in antibody-screening assay. The purified chimera antigen reacted with all the thirty-eight HIV-1 positive serum samples, the two HIV-2 serum samples, and had no cross-reaction with all the eighty-eight normal healthy serum sample. The results indicated that this recombinant chimera HIV-1/HIV-2 envelope protein could be useful for diagnostic purposes of HIV infection.

AIDS Serodiagnosis↗

PubMed1998

A model system for studying the integration of molecular biology databases.

MOTIVATION: Integration of molecular biology databases remains limited in practice despite its practical importance and considerable research effort. The complexity of the problem is such that an experimental approach is mandatory, yet this very complexity makes it hard to design definitive experiments. This dilemma is common in science, and one tried-and-true strategy is to work with model systems. We propose a model system for this problem, namely a database of genes integrating diverse data across organisms, and describe an experiment using this model. RESULTS: We attempted to construct a database of human and mouse genes integrating data from GenBank and the human and mouse genome-databases. We discovered numerous errors in these well-respected databases: approximately 15% of genes are apparently missing from the genome-databases; links between the sequence and genome-databases are missing for another 5-10% of the cases; about a third of likely homology links are missing between the genome-databases; 10-20% of entries classified as 'genes' are apparently misclassified. By using a model system, we were able to study the problems caused by anomalous data without having to face all the hard problems of database integration. CONTACT: nat@jax.org

Animals↗

PubMed1998

Determinants of patient choice of medical provider: a case study in rural China.

This study examines the factors that influence patient choice of medical provider in the three-tier health care system in rural China: village health posts, township health centres, and county (and higher level) hospitals. The model is estimated using a multinomial logit approach applied to a sample of 1877 cases of outpatient treatment from a household survey in Shunyi county of Beijing in 1993. This represents the first effort to identify and quantify the impact of individual factors on patient choice of provider in China. The results show that relative to self-pay patients, Government and Labour Health Insurance beneficiaries are more likely to use county hospitals, while patients covered by the rural Cooperative Medical System (CMS) are more likely to use village-level facilities. In addition, high-income patients are more likely to visit county hospitals than low-income patients. The results also reveal that disease patterns have a significant impact on patient choice of provider, implying that the ongoing process of health transition will lead people to use the higher quality services offered at the county hospitals. We discuss the implications of the results for organizing health care finance and delivery in rural China to achieve efficiency and equity.

China↗

PubMed1998

Progestin receptor isoforms and prostaglandin dehydrogenase in the endometrium of women using a levonorgestrel-releasing intrauterine system.

This study has examined endometrial tissue in 14 normal women prior to insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) and thereafter longitudinally for up to 12 months post-insertion. The specific endpoints examined by immunohistochemistry were progesterone receptor (PR) subtypes A + B, oestrogen receptor (ER) and prostaglandin dehydrogenase (PGDH). Two antiprogesterone receptor antibodies, one specific to PR(B) subtype and the other to PR subtype A + B, were employed to examine the localization of both PR isoforms. The activity of PGDH, a progesterone dependent enzyme, was also measured. ER and PR(A+B) and PR subtype B were significantly down-regulated in glands and stroma in the presence of continuous intrauterine LNG delivery. There was an apparent increase in PR(A) immunoreactivity in endometrial glands between 6 and 12 months post-insertion. Consistent with down-regulation of both isoforms of PR was reduced glandular PGDH immunostaining following LNG-IUS insertion, and PGDH activity (as measured by metabolism of excess substrate in vitro). Furthermore, PGDH activity, known to be localized in the glands, significantly increased (P < 0.05) at 12 months post-insertion, coinciding with the observed increase in glandular PR(A+B) immunoreactivity at this time. Since the LNG-IUS suppresses the PR(B) so strongly, PR(A) is likely to be the subtype that mediates long term LNG action in the endometrium. PR(B) is the more suppressed of the two subtypes, and only PR(A) rises along with PGDH activity. Alterations to normal endometrial morphology and function, e.g. perturbation of normal sex steroid receptor expression, following exposure to high concentrations of local LNG, may play a role in the aetiology of bleeding disorders associated with the LNG-IUS. Further elucidation of local uterine mediators involved in the mechanism of bleeding problems is required.

Adult↗

PubMed1998

Morphological and functional features of endometrial decidualization following long-term intrauterine levonorgestrel delivery.

Irregular bleeding remains a common reason for the discontinuation of progestin-only contraception. The levonorgestrel releasing intrauterine system (LNG-IUS) has profound morphological effects upon the endometrium. Specific features are gland atrophy and extensive decidual transformation of the stroma. Morphological changes in the endometrium may be associated with perturbation of mechanisms regulating normal endometrial function. This study describes endometrial stromal and glandular features prior to and up to 12 months following insertion of the LNG-IUS. Comparison is made with first trimester decidua. In order to elucidate further mechanisms governing endometrial function with local intrauterine delivery of LNG, we here report histological features consistent with decidualization; a significant increase in granulocyte-macrophage colony stimulating factor (GM-CSF) immunoreactivity in decidualized stromal cells; glandular and stromal prolactin receptor expression and an infiltrate of CD56 + large granular lymphocytes and CD68 + macrophages. We are unaware of previous reports which have documented longitudinally both morphological and functional observations in endometrium exposed to local intrauterine levonorgestrel delivery. These studies demonstrate that long-term administration of intrauterine levonorgestrel results in features of altered morphology and function. No correlation was apparent between the end points in the study and the bleeding patterns described by the subjects. Further evaluation of these features in the context of menstrual bleeding experience may contribute to a better understanding of this troublesome side-effect which often leads to dissatisfaction and discontinuation of the intrauterine system.

Adult↗

PubMed1998

Precocious expression of T cell functional response genes in vivo in primitive thymocytes before T lineage commitment.

The genes encoding effector molecules of mature T cells, IL-2, perforin and IL-4, were found to be expressed in vivo in the most primitive subsets of thymocytes of adult mice. These subsets have previously been identified by their cell surface markers and by their expression of other T lineage-associated genes. While IL-2, perforin and IL-4 are expressed in distinct patterns, all three are expressed before the induction of RAG-1 and pre-TCR alpha mRNA expression, and are confined to subsets of cells that apparently have not yet undergone commitment to the T lineage. Thus, expression of T cell response genes appears to be one of the earliest markers of lymphocyte differentiation. Activation events marked by CD69 induction occur in these early cell types, but the response gene expression by these cells is separable from CD69 expression. IL-2 and perforin are induced again much later in thymocyte development, during TCR-dependent repertoire selection. At those stages, IL-2 protein and RNA levels per cell are higher, but the fraction of cells expressing IL-2 appears to be much lower than in the most immature stages. In addition, a striking feature of the immature populations is the robust IL-2 expression by presumptive immature NK cells. These findings are discussed in terms of the developmental origins of lineage specificity in T cell response gene regulation.

Animals↗

PubMed1998

Stability study of LSD under various storage conditions.

A controlled study was undertaken to determine the stability of LSD in pooled urine samples. The concentrations of LSD in urine samples were followed over time at various temperatures, in different types of storage containers, at various exposures to different wavelengths of light, and at varying pH values. LSD concentrations were measured quantitatively by the Abuscreen RIA and by HPLC using a fluorescence detection method. Good correlation was observed between the immunoassay and the fluorescent integrity of the LSD molecule. Thermostability studies were conducted in the dark with various containers. These studies demonstrated no significant loss in LSD concentration at 25 degrees C for up to 4 weeks. After 4 weeks of incubation, a 30% loss in LSD concentration at 37 degrees C and up to a 40% at 45 degrees C were observed. Urine fortified with LSD and stored in amber glass or nontransparent polyethylene containers showed no change in concentration under any light conditions. Stability of LSD in transparent containers under light was dependent on the distance between the light source and the samples, the wavelength of light, exposure time, and the intensity of light. After prolonged exposure to heat in alkaline pH conditions, 10 to 15% of the parent LSD epimerized to iso-LSD. Under acidic conditions, less than 5% of the LSD was converted to iso-LSD. We also demonstrated that trace amounts of metal ions in buffer or urine could catalyze the decomposition of LSD and that this process can be avoided by the addition of EDTA. This study demonstrates the importance of proper storage conditions of LSD in urine in order to insure proper analytical testing results over time.

Chlorides↗

PubMed1998

Progesterone receptor subtype B is differentially regulated in human endometrial stroma.

Two anti-progesterone receptor (PgR) antibodies, a new one specific to PgRB, the other to PgR subtypes A + B, have been used to examine the cellular location of PgR subtypes A and B in normal endometrium throughout the menstrual cycle and in early human decidua by standard immunohistochemical techniques. PgR(A+B) is the receptor detected by the antibody recognizing both isoforms of the receptor. PgRB is the receptor detected by the new antibody specific to the B isoform. Since it is not possible to raise antibody specific to PgR subtype A, all immunohistochemical analysis of the PgRA subtype is by subtractive inference. Thus we refer to PgRA as the subtype responsible for positive immunoreactivity when the PgRB subtype cannot be specifically detected. Endometrial biopsies were collected from 40 women with regular menses (n = 5 each stage of cycle: menstrual; early, mid and late proliferative; ovulatory; early, mid, and late secretory). Decidual tissue was obtained from 10 women undergoing first trimester surgical termination of pregnancy. As previously reported, the PgR(A+B) antibody stained glandular and stromal nuclei during the proliferative phase but only stromal nuclei during the secretory phase and early pregnancy. The new PgRB antibody also stained both cell types intensely during the proliferative phase, but failed to stain either stromal or glandular nuclei strongly during the secretory phase and early pregnancy. We concluded that, while both PgR subtypes were present in glands and stroma in the proliferative phase, and both subtypes were dramatically reduced in the glands during the secretory phase, PgRA remained as the predominant type in the stroma during the secretory phase and early pregnancy. The profound effects of progesterone on endometrium during the secretory phase and early pregnancy appear to be mediated primarily by PgRA in the stroma.

Adult↗

PubMed1998

Post-isolation inducible nitric oxide synthase gene expression due to collagenase buffer perfusion and characterization of the gene regulation in primary cultured murine hepatocytes.

The traditional two-step EGTA/collagenase method is widely used in studying nitric oxide (NO) production in hepatocytes. The present study first revealed that hepatocytes isolated by this method spontaneously express an iNOS mRNA. Thereafter, based on this novel finding, we characterized the expression and regulation of the gene in primary cultured hepatocytes. Using Northern blot analysis, the iNOS mRNA was observed 4 h after isolation, reached peak at 8 h, and declined to an undetectable level after 24 h. iNOS gene expression was shown to be serum-independent and not due to lipopolysaccharide contamination. Time-course analysis of the effects of actinomycin D demonstrated that the increase in iNOS transcripts is the result of an accompanying great increase in iNOS gene transcription and lower iNOS mRNA stability; also blockage by cycloheximide suggests that it is dependent on de novo protein synthesis. Inhibition by pyrrolidine dithiocarbamate, a NF-kappaB/c-rel inhibitor, further implies the involvement of NF-kappaB/c-rel. To clarify reason(s) for the induction, hepatocytes were isolated with the collagenase buffer perfusion step omitted. As a consequence, iNOS mRNA was undetectable in the hepatocytes. These findings show that the traditional hepatocyte-isolation culture does indeed transiently express a serum-independent but de novo protein synthesis-dependent iNOS mRNA due to collagenase (type IV) buffer perfusion.

Animals↗

PubMed1998

Wavelet analysis of embolic heart sound detected by precordial Doppler ultrasound during continuous venous air embolism in dogs.

UNLABELLED: The spectrum of the embolic heart sounds (EHS) detected by precordial Doppler ultrasound has been previously characterized, but only on small volumes of venous air embolism (VAE). We sought to determine whether real-time wavelet analysis is useful in analyzing the signals of EHS and whether the embolic power of the EHS for larger volumes of air is proportionate to the volume of VAE that has been reported for small volumes of VAE. A series of small air boli (0.01, 0.02, 0.05, 0.07, 0.1, 0.15, 0.2, 0.3, 0.4, and 0.8 mL), followed by continuous infusion of larger volumes of air (0.8, 1.6, 2.4, 4.8, and 9.6 mL), was injected into the external jugular vein through a central catheter in seven pentobarbital-anesthetized dogs. We measured the spectrum of the Doppler heart sound (DHS) in a real-time manner by using wavelet analysis at different scales. Wavelet analysis at scale = 1 yielded satisfactory results in distinguishing abnormal EHS from normal DHS with high sensitivity (100%) and good positive predictive value (100%) compared with the conventional method, which requires an anesthesiologist to listen to the audio DHS signals in a real-time manner. There was a linear relationship (y = 1.08x + 7.89, r = 0.75, P < 0.001) between the cumulative embolic power of the EHS and the air volume introduced in the form of either bolus or continuous infusion. The 95% confidence intervals for slope and intercept were 0.89-1.27 and 7.65-8.13, respectively. Our results suggest that wavelet analysis is effective as a real-time monitor and that it is possible to distinguish larger volumes of air emboli based on previous injections of small volumes of air. IMPLICATIONS: The real-time wavelet analysis of the heart sound detected by precordial Doppler ultrasound may be useful in estimating larger volumes of air emboli based on previous injections of small volumes of air in anesthetized dogs.

Animals↗

PubMed1998

Inhibitory effect of enalapril on neurally mediated syncope in elderly patients.

A dramatic increase in catecholamine (CA) concentration is believed to be a primary trigger of the neurally mediated syncope (NMS) in elderly subjects. The hypercontractile state of the heart might be alleviated by angiotensin-converting enzyme (ACE) inhibitor through depression of CA release from the sympathetic nerve ending. Thus ACE inhibitor might have positive effect on the prevention of NMS. In this study, 24 elderly subjects who had reproducible NMS induced with head-up tilt test (HUT) were randomized and double-blind divided into placebo and ACE-inhibitor groups. The plasma CA concentration [norepinephrine (NE) and epinephrine (E)] were measured during HUT, and the effects of enalapril on NMS were observed in the two groups. Before administration of enalapril, plasma CA concentrations were significantly increased during HUT compared with those in the supine position; In contrast, administration of the enalapril (10 mg/day) for >1 year inhibited the concentration of plasma CA increase and prevented syncope in all 12 patients (p < 0.05); however, placebo had no effect on plasma CA concentrations and syncope disappeared in only two of 12 patients after administration of placebo. From this study, we conclude that enalapril can prevent NMS in patients, presumably because of its part in the inhibition of CA release from sympathetic nerve endings.

Aged↗

PubMed1998

The physiologic consequences of macrophage pacification during severe acute pancreatitis.

Macrophage overproduction of inflammatory mediators is detrimental in the progression of acute pancreatitis. Although inhibition of inflammatory mediators has been shown to decrease the severity of experimental pancreatitis and improve overall survival, less is known about the mechanism by which blockade produces these benefits. Prior to the induction of lethal acute pancreatitis, rats were randomized to receive a single dose (.01, .1, 1.0, or 10 mg/kg) of a macrophage-pacifying compound (CNI-1493) or vehicle. Escalating doses provided incremental increases in survival from 10% (vehicle) to a maximum of 70% (CNI-1493, 1.0 mg/kg). To evaluate the physiologic mechanism responsible for the improved survival, continuous arterial blood pressure, serial hematocrit, ascites volume, pancreatic edema, bronchoalveolar leukocytes and protein, and pancreatic histology were determined in additional rats receiving CNI-1493 (1.0 mg/kg). Serum tumor necrosis factor-alpha and nitrites were also determined to assess the mechanism of action of CNI-1493. Macrophage pacification decreased pancreatitis severity as determined by enzyme release and pancreatic histology score. Ascites volume and bronchoalveolar protein levels were also decreased, indicating that CNI-1493 prevents the loss of circulating blood volume and maintains hematocrit and mean arterial pressure, thus improving survival. CNI-1493 prevented the increase of serum tumor necrosis factor-alpha but not serum nitrites, implicating macrophage-derived cytokines and not nitric oxide in the pathogenesis of physiologic decompensation and death in this model of pancreatitis.

Acute Disease↗

PubMed1998

CNI-1493 attenuates hemodynamic and pro-inflammatory responses to LPS.

The increased production of pro-inflammatory cytokines and nitric oxide have been postulated to contribute to the deleterious sequella of LPS administration. To date, clinical strategies to control these responses using individual specific inhibitors have been disappointing. The aim of the present study was to determine whether a tetravalent guanylhydrazone compound (CNI-1493) attenuates LPS-induced stress responses by suppressing multiple inflammatory mediators. Rats were injected intravenously with either CNI-1493 (10 mg/kg) or vehicle (1 mL NaCl) 60 min prior to the injection of LPS (100 microg/100 g body weight). LPS produced a 20% decrease in mean arterial blood pressure and a significant increase in circulating TNF-alpha levels as well as in tissue content of TNF-alpha, IL-1beta, and IL-6. This was associated with a marked increase in lung and gut apoptosis and myeloperoxidase (MPO) activities as well as with an increase in lung and spleen nitric oxide end products (NOx). Pretreatment with CNI-1493 attenuated the LPS-induced drop in mean arterial blood pressure (MABP) and blunted (40%) the rise in circulating TNF-alpha levels. CNI-1493 attenuated the LPS-induced increase in tissue cytokine (TNF-alpha, IL-1beta, and IL-6) content in lung and spleen but did not alter that of liver or gut. CNI-1493 pretreatment protected both lung and gut from LPS-induced apoptosis and in addition attenuated the rise in MPO activity in the gut. These results suggest diverse effects of CNI-1493 that are tissue specific and that confer protection against the hemodynamic and inflammatory responses to LPS.

Animals↗

PubMed1998

Hypophysectomy, high tumor necrosis factor levels, and hemoglobinemia in lethal endotoxemic shock.

Experimental models of lethal endotoxemia in rodents are widely used to delineate pathogenic mechanisms of inflammation, sepsis, and septic shock. One long-standing but poorly understood observation is that removal of the pituitary gland (hypophysectomy) renders experimental animals 1,000-fold more sensitive to the lethal sequelae of lipopolysaccharide (LPS). Previous explanations for this phenomenon focused on hypophysectomy-induced deficiencies of corticosteroids, because glucocorticoids effectively suppress the synthesis of tumor necrosis factor (TNF), which is a primary mediator of LPS lethality. We measured LPS-stimulated macrophage TNF release in the presence of serum from hypophysectomized rats to detect the appearance of an inducible 65 kDa protein that enhances TNF release. Surprisingly, the N-terminal amino acid sequence analysis of the isolated, purified protein revealed its identity as hemoglobin. Hypophysectomy significantly increases serum hemoglobin levels (control hemoglobin = 103+/-18 microg/mL versus hypophysectomized serum hemoglobin = 279+/-13 microg/mL; p < .05). Purified hemoglobin enhances TNF synthesis in LPS-stimulated macrophages by at least 1,000-fold, which is specifically inhibited by antihemoglobin antibodies. Thus, hemoglobin mediates increased TNF synthesis in endotoxemic, hypophysectomized rats. This mechanism of increased TNF release has potential implications for patients with hemoglobinemia following blood transfusion, surgery, injury, infection, or other conditions that can be associated with endotoxemia and sepsis.

Animals↗