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Biomedical subjects

W Cheng

Publications and source records attributed to W Cheng.

At least 127 records · Page 7Linked to original sources
PubMed1995

Contribution of opening and closing of lung units to lung hysteresis.

The recruitment and derecruitment of lung units is one explanation of the hysteresis observed in an excised lung during inflation and deflation. A simplified model has been proposed in which the recruitment-derecruitment process is a function of end-expiratory pressure (Frazer, D.G., K.C. Weber and G.N. Franz, Respir. Physiol. 61: 277-288, 1985). The object of this study was to test this model with three experimental procedures. During the first set of experiments, progressively larger pressure-volume (PL-VL) loops were recorded with end-expiratory pressure held at either -5 cmH2O, where all lung units are assumed to be closed, or +5 cmH2O, where all recruited lung units are assumed to be open. In the first case hysteresis is maximal, in the second, minimal. The difference in hysteresis is presumed to arise from the recruitment-derecruitment process. In the second set of experiments, excised lungs are slowly inflated and then deflated at a constant rate while constant-amplitude sinusoidal volume oscillations are superimposed. The end-expiratory pressure of the superimposed loops gradually rose as the lung was inflated and fell as the lung was deflated. Hysteresis was minimal when end-expiratory pressure was above 4 +/- 1 cmH2O even as peak-to-peak loop pressure greatly varied. This supports the notion of an end-expiratory pressure dependent mechanism of recruitment/derecruitment. During the third set of experiments lungs were inflated to either 50%, 75%, or 100% TLC. Volumes of air were then withdrawn and replaced so that the initial volume was restored in sinusoidal fashion as the amplitude of the volume excursions increased. For PL-VL loops with end-expiratory pressures between +4 and -2 cmH2O, pressure amplitudes rose and the hysteresis index (loop area/tidal volume) increased, regardless of the initial lung volume. These results are consistent with the previously described model of Frazer et al. (1985) which assumed that PL-VL curves can be divided into an 'opening' region, an 'open' region and a 'closing' region and that the demarcation of these regions depends on transpulmonary pressure, specifically end-expiratory pressure, and to a much lesser degree on lung volume.

Animals↗
PubMed1995

Myocardial infarction and the myocyte IGF1 autocrine system.

To determine the effects of acute myocardial infarction on the extent and distribution of mural stress on surviving myocardial tissue, coronary artery occlusion was surgically produced in rats. Following haemodynamic measurements in vivo, the characteristics of cardiac anatomy were determined and found to consist of an increase in mid-chamber lumenal diameter and a decrease in wall thickness. The combination of these phenomena resulted in an eight-fold increase in diastolic wall stress on the remaining viable portion of the wall and severe impairment of left and right ventricular performance. Since insulin-like growth factor-1 (IGF1) and its receptor (IGF1R) are required for cell growth in vitro, the possibility was raised that an autocrine IGF1-IGF1R system may be present in vivo and may become activated in viable ventricular myocytes shortly after infarction. Therefore, the unaffected myocytes of the left ventricle were enzymatically dissociated and the expression of IGF1R and IGF1 mRNAs were measured at 12 h and at 1, 2-3, and 7 days after surgery. The level of IGF1R mRNA increased at 12 h and remained elevated at 1 and 2-3 days following coronary artery ligation. In addition, an increased level of IGF1R protein was found on these cells. This phenomenon was coupled with the enhanced expression of IGF1 mRNA in the muscle cells at all points. Thus, the marked elevation in ventricular loading after coronary occlusion may activate the IGF1-IGF1R autocrine system of the unaffected cells, modulating the cellular growth processes implicated in short-term ventricular remodelling of the infarcted heart.

Animals↗
PubMed1995

Isolation of NAD cycle mutants defective in nicotinamide mononucleotide deamidase in Salmonella typhimurium.

The NAD or pyridine nucleotide cycle is the sequence of reactions involved in the breakdown of NAD to nicotinamide mononucleotide (NMN) and regeneration of NAD. This cycle is fivefold more active during aerobic growth of Salmonella typhimurium and under this condition breaks down half of the NAD pool every 90 min. DNA ligase is known to convert NAD to NMN but is only a minor contributor to the NAD cycle during aerobic growth. The dominant aerobic route of NMN formation is otherwise uncharacterized. Accumulated NMN generated by either of these routes is potentially dangerous in that it can inhibit the essential enzyme DNA ligase. The reactions which recycle NMN to NAD may serve to minimize the inhibition of ligase and other enzymes by accumulated NMN. The predominant recycling reaction in S. typhimurium appears to be NMN deamidase, which converts NMN directly to the biosynthetic intermediate nicotinic acid mononucleotide. Mutants defective in this recycling step were isolated and characterized. By starting with a ligase-deficient (lig mutant) parent strain that requires deamidase to assimilate exogenous NMN, two classes of mutants that are unable to grow on minimal NMN media were isolated. One class (pncC) maps at 83.7 min and shows only 2% of the wild-type levels of NMN deamidase. Under aerobic conditions, a lig+ allele allows a pncC mutant to grow on NMN and restores some deamidase activity. This growth ability and enzyme activity are not found in lig+ strains grown without oxygen. This suggests that the existence of a second NMN deamidase (pncL) dependent on ligase and stimulated during aerobic growth. The second class of mutants (pncD) gains a requirement for isoleucine plus valine with growth in the presence of exogenous NMN. We propose that pncD mutations reduce the activity of an ilv biosynthetic enzyme that is naturally sensitive to inhibition by NMN.

Amidohydrolases↗
PubMed1995

Dexamethasone enhances accumulation of cholesteryl esters by human macrophages.

The effects of dexamethasone on lipid accumulation by human monocyte-derived macrophages were investigated. Preincubation of macrophages with dexamethasone for a period of 16-20 h resulted in a reproducible increase (3.5-fold) in the incorporation of oleate into cholesteryl esters. The effect was specific because no alterations were observed in oleate incorporation into triglycerides or phospholipids. Measurement of cellular cholesteryl esters indicated a fourfold increase after preincubation with dexamethasone. This increase was mediated by opposite effects on synthesis and breakdown of these lipids. Dexamethasone produced a 60% increase in activity of the enzyme acyl-CoA: cholesterol O-acyltransferase (ACAT), active in synthesis of cholesteryl esters, and a 40% decrease in that of neutral cholesteryl esterase, active in cholesteryl ester breakdown. The increased ACAT activity appeared to reflect increased mRNA for the enzyme. The effects of dexamethasone on cholesteryl ester accumulation by macrophages reached statistical significance at a concentration of 100 nM. They were dose dependent, and saturation was observed at around 1 microM. The effects were significant at low concentrations of cholesterol in the medium. At high-medium cholesterol, there was a large cholesterol-induced increase in ACAT activity that obscured most of the effect of dexamethasone. In general, the data suggest that high glucocorticoid levels enhance lipid accumulation by macrophages and thus would have an atherogenic action that is independent of serum cholesterol.

Cell Differentiation↗
PubMed1995

Myocyte performance during evolution of myocardial infarction in rats: effects of propionyl-L-carnitine.

To determine whether alterations in the mechanical properties and calcium transients of myocytes are important factors in the evolution of the postinfarcted heart, these physiological parameters were measured in the viable muscle cells of the left ventricle 6 h, 2-3 days, 1 wk, and 1 mo after coronary artery occlusion and the documentation of left ventricular failure. In addition, the effects of propionyl-L-carnitine (PLC) on shortening properties and calcium dynamics of single myocytes were established to demonstrate whether the potential increase in ATP generation by this intervention improved myocyte cell function. Myocardial infarction was associated with a progressive increase in length of the spared myocytes, whereas the changes in myocyte diameter were apparent only at the 1-mo interval. Mechanically, myocyte shortening was decreased 43% at 6 h, 34% at 2-3 days, 26% at 1 wk, and 41% at 1 mo after infarction. Similar abnormalities were noted in the velocity of myocyte shortening. Peak systolic calcium was decreased at all intervals after infarction. In contrast, diastolic calcium remained within control values. PLC was capable of ameliorating the mechanical behavior and calcium transients of myocytes, particularly 1 mo after infarction. Thus alterations in muscle cell performance may be important determinants in the development and progression of ischemic cardiomyopathy, and interventions improving myocyte contractility may interfere with the unfavorable outcome of the disease.

Animals↗
PubMed1995

Fibroblast proliferation during myocardial development in rats is regulated by IGF-1 receptors.

To determine whether the growth of cardiac fibroblasts during development is modulated by the insulin-like growth factor (IGF)-1 receptor (IGF-1R), the expression of IGF-1, IGF-2, and IGF-1R was determined in fibroblasts from fetal and postnatal hearts. The expression of proliferating cell nuclear antigen (PCNA) and DNA polymerase-alpha was also evaluated in combination with the estimation of DNA replication. In comparison with fetal hearts, at postnatal day 21, fibroblast expression of IGF-1R mRNA, IGF-2, PCNA, and DNA polymerase-alpha was reduced by 77, 70, 80, and 86%, respectively. Moreover, IGF-1R protein decreased by 48% at 21 days. Bromodeoxyuridine labeling decreased by 88 and 89% in the left and right ventricle, respectively, at this time. Two different antisense oligodeoxynucleotides to IGF-1R reduced DNA replication by 60 and 44% in fibroblasts in culture. In addition, this intervention markedly attenuated the growth response of fibroblasts to IGF-1 or serum. In conclusion, the IGF-1R system appears to play a major role in the regulation of fibroblast growth in the heart in vivo.

Animals↗
PubMed1995

Identification and activation of autocrine renin-angiotensin system in adult ventricular myocytes.

To date, the demonstration that the molecular components of the renin-angiotensin system (RAS) are present in adult ventricular myocytes is lacking. In addition, whether the RAS is upregulated under conditions of overload and myocyte hypertrophy in vivo remains to be determined. By employing an in vivo model of ischemic cardiomyopathy in rats, we document that adult myocytes express genes for renin, angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin II (ANG II) receptors. Moreover, renin, ACE, and ANG II receptor mRNAs increased in stressed myocytes undergoing cellular hypertrophy. At the protein level, the percentage of myocytes containing renin, ANG I, and ANG II was significantly increased in the overloaded heart. The number of binding sites for ANG II per myocyte also markedly increased under this setting. These results provide direct evidence of the existence of a myocyte RAS, which may be activated in pathological states of the heart to support myocyte growth and contractile function.

Angiotensinogen↗
PubMed1995

Stretch-induced programmed myocyte cell death.

To determine the effects of loading on active and passive tensions, programmed cell death, superoxide anion formation, the expression of Fas on myocytes, and side-to-side slippage of myocytes, papillary muscles were exposed to 7-8 and 50 mN/mm2 and these parameters were measured over a 3-h period. Overstretching produced a 21- and a 2.4-fold increase in apoptotic myocyte and nonmyocyte cell death, respectively. Concurrently, the generation of reactive oxygen species increased 2.4-fold and the number of myocytes labeled by Fas protein 21-fold. Moreover, a 15% decrease in the number of myocytes included in the thickness of the papillary muscle was found in combination with a 7% decrease in sarcomere length and the inability of muscles to maintain stable levels of passive and active tensions. The addition of the NO-releasing drug, C87-3754, prevented superoxide anion formation, programmed cell death, and the alterations in active and passive tensions with time of overloaded papillary muscles. In conclusion, overstretching appears to be coupled with oxidant stress, expression of Fas, programmed cell death, architectural rearrangement of myocytes, and impairment in force development of the myocardium.

Animals↗
PubMed1995

Ventricular remodeling in global ischemia.

To determine the effects of chronic constriction of the left coronary artery on the function and structure of the heart, coronary artery narrowing was surgically induced in rats and ventricular pump performance, extent and distribution of myocardial damage, and the hypertrophic and hyperplastic response of myocytes were examined. Alterations in cardiac hemodynamics were found in all rats, but the characteristics of the physiological properties of the heart allowed a separation of the animals into two groups which exhibited left ventricular dysfunction and failure, respectively. Left ventricular hypertrophy occurred in both groups and was characterized by ventricular dilatation and wall thinning which were more severe in the failing animals. Multiple foci of myocardial damage across the wall were seen in all animals but tissue injury was more prominent in the endomyocardium and in failing rats. The anatomical and hemodynamic changes resulted in a significant increase in diastolic wall stress which paralleled the depression in ventricular performance. Myocyte cell loss and myocyte cellular hypertrophy were more severe with ventricular failure than with dysfunction. Finally, diastolic overload appeared to be coupled with activation of the DNA synthetic machinery of myocytes and nuclear mitotic division. In conclusion, a fixed lesion of the left coronary artery leads to abnormalities in cardiac dynamics with marked increases in diastolic wall stress and extensive ventricular remodeling in spite of compensatory myocyte cellular hypertrophy and hyperplasia in the remaining viable tissue.

Animals↗
PubMed1995

Down-regulation of the IGF-1 system parallels the attenuation in the proliferative capacity of rat ventricular myocytes during postnatal development.

BACKGROUND: Insulin-like growth factor-1 receptor (IGF-1R) and its ligand (IGF-1) have been implicated in the growth of several cell types, including ventricular myocytes. However, the growth-promoting effect of this pathway on myocyte hypertrophy and hyperplasia has not been determined. During early postnatal development, myocyte cell volume increases nearly 25-fold, and myocyte proliferation is markedly attenuated, so a progressive decrease in this signaling mechanism will indicate that the IGF-1-IGF-1R system is mostly involved in cell proliferation. Conversely, a continuous increase in the expression of IGF-1 and IGF-1R in myocytes with maturation will suggest its involvement in cellular hypertrophy. DESIGN: Myocytes were isolated from fetal rats and from rats at 1, 5, 11, 21, 35, and 60 days of age. Total RNA was extracted from these cells, and the expression of IGF-1, IGF-2, IGF-1R, and DNA polymerase alpha was measured by reverse transcriptase-PCR. IGF-1R mRNA levels were also determined by RNase protection assay, and the changes in IGF-1R protein were determined by the cross-linking technique. Finally, the expression of late growth-related genes was determined and compared with the fraction of muscle cells synthesizing DNA. These analyses were restricted to the left ventricular free wall and septum combined. RESULTS: Myocardial development was characterized by a progressive decrease in the expression of late growth-related genes in myocytes, which was particularly evident at 21 days after birth and persisted up to 2 months of age. The expression of IGF-2 in these cells decreased at birth, whereas the attenuation in IGF-1 mRNA became apparent a few days later during postnatal development. The induction of IGF-1R at the message and protein levels decreased by 11 days, and this phenomenon was more evident at the subsequent age intervals. Moreover, DNA synthesis in myocytes was sharply reduced at 21 days after birth. CONCLUSIONS: In conclusion, the decline in myocyte proliferation with cardiac development appears to be coupled with attenuation of the IGF-1-IGF-1R system, which may condition the changes in late growth-regulated genes, DNA replication, and cellular mitotic division in the myocardium.

Aging↗
PubMed1995

Myocyte nuclear mitotic division and programmed myocyte cell death characterize the cardiac myopathy induced by rapid ventricular pacing in dogs.

BACKGROUND: Observations in humans have raised the possibility that idiopathic dilated cardiomyopathy is characterized by myocyte cell loss and cell proliferation, which contribute to wall thinning and chamber dilation. Moreover, the mechanism of myocyte cell death in this patient population has been unclear. Because rapid ventricular pacing in dogs leads to a dilated myopathy that mimics the idiopathic form in man, this animal model was used to demonstrate whether myocyte nuclear mitotic division and programmed myocyte cell death occur in this setting. Additionally, the expression of proliferating cell nuclear antigen (PCNA) and Fas protein in myocytes was examined as a molecular indicator of the activation of the cell cycle and apoptotic cell death, respectively. EXPERIMENTAL DESIGN: Mongrel dogs were chronically instrumented for measurements of systemic hemodynamics and for left ventricular pacing. At sacrifice, myocardial samples were obtained for the estimation of the number of myocytes and interstitial cells showing mitosis and for the detection of DNA laddering. In addition, the number of myocyte nuclei exhibiting DNA strand breaks, as well as the frequency of myocytes labeled by PCNA and Fas protein, was determined. Finally, the distribution of nuclei in enzymatically dissociated myocytes was evaluated. RESULTS: Pacing-induced heart failure was characterized by DNA fragmentation and by 3700 myocytes per million cells undergoing apoptotic cell death. This phenomenon was accompanied by 11,000 cells per million expressing Fas protein. Concurrently, 22 and 17 myocytes and interstitial cells per million showed nuclear mitotic division, whereas no changes in the relative proportions of mononucleated and multinucleated myocytes were detected. Moreover, PCNA-labeled myocytes accounted for 40,000 cells per million. CONCLUSIONS: In conclusion, the induction of PCNA and Fas may be linked to the activation of myocyte proliferation and programmed cell death in the myocardium with rapid ventricular pacing, and these two cellular responses may play a key role in the development of the congestive dilated myopathy.

Animals↗
PubMed1994

Structural organization of the human type VII collagen gene (COL7A1), composed of more exons than any previously characterized gene.

The human type VII collagen (COL7A1) gene is the locus for mutations in at least some cases of dystrophic epidermolysis bullosa. Here we describe the entire intron/exon organization of COL7A1, which is shown to have 118 exons, more than any previously described gene. Despite this complexity, COL7A1 is compact. Consisting of 31,132 bp from transcription start site to polyadenylation site, it is only about three times the size of type VII collagen mRNA. Thus, COL7A1 introns are small. A 71-nucleotide COL7A1 intron is the smallest intron yet reported in a collagen gene, and only one COL7A1 intron is greater than 1 kb in length. All exons in the COL7A1 triple helix coding region that do not begin with sequences corresponding to imperfections of the triple helix begin with intact codons for Gly residues of Gly-X-Y repeats. This is reminiscent of the structure of fibrillar rather than other nonfibrillar collagen genes. In addition, the COL7A1 triple helix coding region contains many exons of recurring sizes (e.g., 25 exons are 36 bp, 12 exons are 45 bp, 8 exons are 63 bp), suggesting an evolutionary origin distinct from those of other nonfibrillar collagen genes. Sequences from the 5' portion of COL7A1 are presented along with the 3766-bp intergenic sequence, which separates COL7A1 from the upstream gene encoding the core I protein of the cytochrome bc1 complex. The COL7A1 promoter region is found to lack extensive homologies with promoter regions of other genes expressed primarily in skin.

Amino Acid Sequence↗
PubMed1994

The effects of nitric oxide inhibition on regional hemodynamics during hyperdynamic endotoxemia.

OBJECTIVE: To determine the effect of the inhibition of nitric oxide (NO) on selective organ blood flow in endotoxin-induced sepsis. DESIGN: Nonrandomized, controlled experiment. SETTING: Animal research facility in Brooklyn, NY. PARTICIPANTS: Eleven mongrel dogs. INTERVENTION: Eleven dogs were divided into one of two groups: a control group (n = 5) and an endotoxin-treated group (n = 6). The animals were anesthetized, and electromagnetic and ultrasonic flow probes were placed on the distal aorta, right internal carotid artery, superior mesenteric artery, and left renal artery. Sepsis was induced with a 60-mg/kg intravenous injection of Escherichia coli endotoxin. When the arterial blood pressure decreased to less than 60 mm Hg despite adequate fluid resuscitation, NO synthesis was inhibited with a 25-mg/kg intravenous administration of NG-monomethyl-L-arginine. After 15 minutes of inhibition, a 400-mg/kg intravenous administration of L-arginine, the substrate of NO synthase enzyme, was given. Physiologic measurements were continued for 15 minutes thereafter. MAIN OUTCOME MEASURES: Heart rate, blood pressure, central venous pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac output, hematocrit, arterial and venous blood gas values, and blood flow measurements of right internal carotid artery, superior mesenteric artery, left renal artery, and distal aorta. RESULTS: Control animals did not demonstrate a significant (P > .05) decrease in blood flow in the internal carotid artery, superior mesenteric artery, and distal aorta after the administration of NG-monomethyl-L-arginine. The endotoxin-treated group showed a significant (P < .05) decrease in organ perfusion when treated with the NO synthase inhibitor, NG-monomethyl-L-arginine. CONCLUSIONS: Inhibition of NO production in the treatment of sepsis caused a significant decrease in blood flow to all vascular beds in vivo. The role, if any, of the inhibition of NO in the treatment of sepsis is questioned.

Amino Acid Oxidoreductases↗
PubMed1994

The IGF-1-IGF-1 receptor system modulates myocyte proliferation but not myocyte cellular hypertrophy in vitro.

In preliminary experiments it was established that the hypertrophic and hyperplastic responses of neonatal cardiac myocytes in culture were associated with enhanced expression of IGF-1 and IGF-1 receptors in these cells. Therefore, to determine the role of IGF-1 receptors on myocyte growth, cells were exposed to antisense oligodeoxynucleotides to IGF-1 receptor mRNA and the effects of this intervention on DNA synthesis, nuclear mitotic division, and changes in the number of myocytes were measured. Moreover, the influence of this procedure on ANF induction and myocyte cell volume was examined. Inhibition of the formation of IGF-1 receptors on myocytes suppressed DNA replication, mitosis, and cell proliferation. In contrast, the antisense treatment did not alter the expression of ANF in myocytes or cellular hypertrophy. Finally, IGF-1 stimulated DNA synthesis in myocytes cultured in serum-free medium, without inducing cellular hypertrophy. In conclusion, ligand activation of IGF-1 receptors on myocytes appears to be coupled with cell proliferation, whereas myocyte cellular hypertrophy seems to be independent from this effector pathway.

Animals↗
PubMed1994

Nitric oxide inhibition in the treatment of the sepsis syndrome is detrimental to tissue oxygenation.

The manifestations of the septic syndrome are thought to be mediated by cytokines through their role in the production of nitric oxide (NO). It is hypothesized that the inhibition of NO production with an inhibitor such as NG-monomethyl-L-arginine (L-NMMA) may be beneficial in the treatment of septic shock. Sepsis was induced by the intravenous administration of Escherichia coli endotoxin (60 micrograms/kg) in six conditioned mongrel dogs (20-24 kg). Mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), and pulmonary artery pressure (PAP) were continuously monitored. Cardiac output (CO), pulmonary capillary wedge pressure (PCWP), and arterial and mixed venous blood gases were obtained every 10 min. When the MAP decreased below 60 mm Hg, NO inhibitor L-NMMA was given by intravenous injection (25 mg/kg). Physiologic parameters were then measured at 2 and 5 min after L-NMMA injection. Subsequently, L-arginine (400 mg/kg), the substrate for the NO synthase enzyme, was administered and measurements were repeated at similar intervals. L-NMMA in septic canines produced a significant increase in MAP and SVR with a significant decrease in CO and tissue oxygenation (DO2 and VO2). These changes were reversed with the administration of L-arginine. There were no significant differences in the PCWP, CVP, PAP, or HR throughout the entire study. These results suggest that the inhibition of NO production by L-NMMA in a septic model produces elevated MAP and SVR at the expense of tissue oxygenation. Thus, its use, as a principal means of therapy for the septic syndrome, may not be appropriate because of detrimental effects on tissue oxygenation.

Animals↗
PubMed1994

Subacute ischemia of the colon esophageal interposition.

The most devastating complication of colon interposition is acute ischemia with colon necrosis. Delayed complications of the interposed colon, including long segment stricturing develop in an occasional patient. Some investigators have speculated that these late complications result from delayed colon ischemia. We believe that these patients represent a small subgroup who have nonnecrotic vascular insufficiency (subacute ischemia) of the interposed colon, which is present from the time of the operation. We reviewed the postoperative contrast radiographic studies of 3 patients with subacute colon ischemia. The radiographic findings are characteristic, and are identical to those seen in ischemic colitis of the nonmobilized colon. They include loss of haustral folds, an ill-defined bowel wall border, and mucosal changes such as "thumbprinting," and "urticaria." Fibrosis and stricturing represent the end-stage of the ischemic process.

Acute Disease↗