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Biomedical subjects

M A Fiedler

Publications and source records attributed to M A Fiedler.

At least 19 recordsLinked to original sources
PubMed2001

Regulation of gap junctional communication by a pro-inflammatory cytokine in cystic fibrosis transmembrane conductance regulator-expressing but not cystic fibrosis airway cells.

Airway inflammation is orchestrated by cell-cell interactions involving soluble mediators and cell adhesion molecules. Alterations in the coordination of the multicellular process of inflammation may play a major role in the chronic lung disease state of cystic fibrosis (CF). The aim of this study was to determine whether direct cell-cell interactions via gap junctional communication is affected during the inflammatory response of the airway epithelium. We have examined the strength of intercellular communication and the activation of nuclear factor-kappaB (NF-kappaB) in normal (non-CF) and CF human airway cell lines stimulated with tumor necrosis factor-alpha (TNF-alpha). TNF-alpha induced maximal translocation of NF-kappaB into the nucleus of non-CF as well as CF airway cells within 20 minutes. In non-CF cells, TNF-alpha progressively decreased the extent of intercellular communication. In contrast, gap junctional communication between CF cells exposed to TNF-alpha remained unaltered. CF results from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Interestingly, transfer of wild-type CFTR into CF cells by adenovirus-mediated infection was associated with the recovery of TNF-alpha-induced uncoupling. These results suggest that expression of functional CFTR is necessary for regulation of gap junctional communication by TNF-alpha. Gap junction channels close during the inflammatory response, therefore limiting the intercellular diffusion of signaling molecules, and thereby the recruitment of neighboring cells. Defects in this mechanism may contribute to the excessive inflammatory response of CF airway epithelium.

Bronchi↗
PubMed2001

Preemptive analgesia applied to postoperative pain management.

Acute postoperative pain can cause detrimental effects on multiple organ systems. To treat pain effectively, a thorough knowledge of the anatomy and physiology of pain and its transmission is necessary. Painful stimuli, like that produced by a surgical incision, can lead to a hyperexcitable state in the spinal cord. This hyperexcitable state can exacerbate postoperative pain. Once the hyperexcitable state has been established, a larger dose of analgesic drug is needed than if hyperexcitability had been prevented. When an analgesic is administered before the bombardment of painful stimuli that occurs with surgical incision, postoperative pain can be greatly diminished. Epidural, intravenous, and intramuscular opioids have been shown to reduce the severity of postoperative pain to a greater extent when administered before surgical stimuli rather than following it.

Analgesics↗
PubMed2001

Thermoregulation: anesthetic and perioperative concerns.

Hypothermia has long been common in anesthesia and has largely been seen as an inconvenience. For many years, it was viewed as inevitable. But hypothermia is much more than an inconvenience, and it is no longer inevitable. Hypothermia is closely associated with significant morbidity both intraoperatively and postoperatively. Hypothermia may begin in the preoperative holding area, so efforts to prevent it should begin there as well. Effective intraoperative and postoperative warming methods are known and commonly available, but they remain underused. Understanding how and why core temperature declines in association with anesthesia and surgery and safe, effective methods to prevent that decline will enable nurse anesthetists and perioperative nurses to increase both the comfort and safety of their patients while reducing costs to the institution.

Anesthesia↗
PubMed2000

Sesquiterpene lactones are potent inhibitors of interleukin 8 gene expression in cultured human respiratory epithelium.

Sesquiterpene lactones, derived from Mexican-Indian medicinal plants, are known to have potent anti-inflammatory properties but the mechanisms of this effect are not completely understood. Recent data demonstrated that sesquiterpene lactones were potent inhibitors of the pro-inflammatory transcription factor NF-kappaB. Because activation of NF-kappaB is involved in the regulation of the chemokine interleukin 8 (IL-8), we hypothesized that the sesquiterpene lactones, isohelenin and parthenolide, would inhibit IL-8 gene expression in cultured human respiratory epithelium. Incubating A549 cells with tumour necrosis factor alpha (TNF-alpha) induced IL-8 mRNA expression and secretion of immunoreactive IL-8. Pretreatment with either isohelenin or parthenolide inhibited TNF-alpha-mediated IL-8 gene expression in a concentration-dependent manner. Pretreatment with either compound inhibited TNF-alpha mediated activation of the IL-8 promoter and TNF-alpha-mediated nuclear translocation of NF-kappaB. In addition, pretreatment with isohelenin or parthenolide inhibited TNF-alpha-mediated degradation of the NF-kappaB inhibitory protein, I-kappaBalpha. We conclude that sesquiterpene lactones are potent in vitro inhibitors of IL-8 gene expression in cultured human respiratory epithelium. The most proximal mechanism of inhibition appears to involve inhibition of I-kappaBalpha degradation. Stabilization of cytoplasmic I-kappaBalpha leads to inhibition of NF-kappaB nuclear translocation and of subsequent IL-8 promoter activation. The ability of sesquiterpene lactones to modulate IL-8 gene expression may explain, in part, their anti-inflammatory effects.

Anti-Inflammatory Agents↗
PubMed2000

Hyperoxia synergistically increases TNF-alpha-induced interleukin-8 gene expression in A549 cells.

Interleukin (IL)-8 is an important mediator of acute lung injury. Hyperoxia induces IL-8 production in some cell types, but its effect on IL-8 gene expression in respiratory epithelium is not well described. In addition, IL-8 gene expression resulting from the combined effects of hyperoxia and proinflammatory cytokines has not been well characterized. We treated cultured respiratory epithelial-like cells (A549 cells) with hyperoxia alone, tumor necrosis factor (TNF)-alpha alone, or the combination of TNF-alpha and hyperoxia and evaluated IL-8 gene expression. Hyperoxia alone had a minimal effect on IL-8 gene expression, and TNF-alpha alone increased IL-8 gene expression in a time-dependent manner. In contrast, the combination of TNF-alpha and hyperoxia synergistically increased IL-8 gene expression as measured by ELISA (TNF-alpha alone for 24 h = 769 +/- 89 pg/ml vs. hyperoxia + TNF-alpha for 24 h = 1, 189 +/- 89 pg/ml) and Northern blot analyses. Experiments involving IL-8 promoter-reporter assays, electromobility shift assays, and Western blot analyses demonstrated that hyperoxia augmented TNF-alpha-mediated activation of the IL-8 promoter by a nuclear factor (NF)-kappaB-dependent mechanism and increased the duration of NF-kappaB nuclear translocation after concomitant treatment with TNF-alpha. Additional reporter gene assays demonstrated, however, that increased activation of NF-kappaB does not fully account for the synergistic effect of hyperoxia and that the NF-IL-6 site in the IL-8 promoter is also required for the synergistic effect of hyperoxia. We conclude that hyperoxia alone has a minimal effect on IL-8 gene expression but synergistically increases IL-8 gene expression in the presence of TNF-alpha by a mechanism involving cooperative interaction between the transcription factors NF-kappaB and NF-IL-6.

Binding Sites↗
PubMed1999

Incomplete regulation of NF-kappaB by IkappaBalpha during respiratory syncytial virus infection in A549 cells.

Respiratory syncytial virus (RSV) infection of airway epithelial cells results in persistent NF-kappaB activation and NF-kappaB-mediated interleukin-8 production. Previous studies in airway epithelial cells demonstrated that tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB activation is transient due to regulation by IkappaBalpha. However, during RSV infection, IkappaBalpha has only a partial inhibitory effect on NF-kappaB activation. Studies presented here demonstrate that neither increased IkappaBalpha production which occurs as a result of RSV-induced NF-kappaB activation nor inhibition of proteasome-mediated IkappaBalpha degradation results in a reversal of RSV-induced NF-kappaB activation. Thus, while manipulation of IkappaBalpha results in reversal of TNF-alpha-induced NF-kappaB activation, manipulation of IkappaBalpha does not result in a reversal of RSV-induced NF-kappaB activation.

DNA-Binding Proteins↗
PubMed1998

Review of chemical, medication, and anesthesia toxicity in the OR.

A host of toxic substances exist in the OR. The toxicity of prep solutions, cleaning chemicals, common medications, and trace anesthetic gases varies greatly. Nurses use, direct others in the use of, or administer potential toxins while breathing air that may be contaminated to some degree with anesthetic vapors. Often, the OR nurse is the neighborhood resource when questions about the toxicity of common chemicals and drugs arise. A general knowledge of the toxicity of these substances improves the nurse's ability to assess the risk from trace anesthetic gases, prevent injury to patients, provide first aid when potentially dangerous exposure occurs, and direct others in the safe use of OR chemicals.

Anesthetics↗
PubMed1998

Essential roles of NF-kappaB and C/EBP in the regulation of intercellular adhesion molecule-1 after respiratory syncytial virus infection of human respiratory epithelial cell cultures.

To determine the molecular mechanism(s) of respiratory syncytial virus (RSV)-induced intercellular adhesion molecule-1 (ICAM-1) upregulation in respiratory epithelial cells (REC; A549 cell cultures), we investigated the roles of the transcription factors NF-kappaB and C/EBP. Increases in ICAM-1 message required de novo mRNA synthesis. ICAM-1 promoter constructs (luciferase reporter gene) transfected into A549 monolayers demonstrated promoter activation following RSV infection. Activation was abolished by site-specific mutation of the NF-kappaB (-228) or C/EBP (-239) sites. These data support the critical role of the activation of NF-kappaB and C/EBP in RSV-induced ICAM-1 expression by REC.

CCAAT-Enhancer-Binding Proteins↗
PubMed1998

Generation of a transgenic mouse with lung-specific overexpression of the human interleukin-1 receptor antagonist protein.

The purpose of the studies described here was to test the hypothesis that overexpression of the human interleukin-1 receptor antagonist (IL-1ra) in the distal airway epithelia of mice would result in amelioration of the inflammatory effects of IL-1alpha. The coding region of the human IL-1ra gene was placed under transcriptional control of the 5' flanking region of the human SP-C gene. Transgenic mice were generated by pronuclear injection of the transgene and identified by Southern blot analysis of genomic DNA. RNA expression of the transgene was confirmed by Northern blot analysis. In order to determine whether expression of the transgene conferred protection against inflammatory stimuli, control and transgenic mice were treated with IL-1alpha by intratracheal instillation. Six hours after treatment, bronchoalveolar lavage was performed, which revealed a statistically significant decrease in the degree of neutrophilia in the transgenic mice as compared with control mice. Furthermore, there was a significant reduction in the whole-lung myeloperoxidase concentration. Reverse transcription-polymerase chain reaction analysis of whole-lung RNA revealed a significant reduction in the messenger RNA/beta-actin ratio of macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-2 in the transgenic animals as compared with controls. The results of these studies indicate that distal airway epithelial cell expression of human IL-1ra results in partial protection from IL-1alpha-induced airway inflammation and injury.

Animals↗
PubMed1998

Inhibition of TNF-alpha-induced NF-kappaB activation and IL-8 release in A549 cells with the proteasome inhibitor MG-132.

The working hypothesis of the studies described herein was that inhibition of proteasome-mediated IkappaB degradation would inhibit TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) activation, interleukin-8 (IL-8) gene transcription, and IL-8 protein release in A549 cells. Mutational analysis of the 5' flanking region of the IL-8 gene confirmed that an intact NF-kappaB site is necessary for TNF-alpha-induced IL-8 gene transcription. The addition of TNF-alpha to A549 cells resulted in rapid loss of IkappaB from the cytoplasm of cells, associated with a corresponding increase in NF-kappaB-binding activity in nuclear extracts from the cells. However, pretreatment of the cells with the proteasome inhibitor N-cbz-Leu-Leu-leucinal (MG-132, 10 microM) reversed the effects of TNF-alpha on IL-8 release from A549 cells (as determined with an enzyme-linked immunosorbent assay [ELISA]) and on IL-8 gene transcription (as determined with reporter-gene assays). MG-132 reversed the effects of TNF-alpha on IkappaB degradation as determined by Western blot analysis. IkappaB phosphorylation and ubiquination were not altered by MG-132, which implies that the effects of MG-132 were secondary to proteasome inhibition. MG-132 also reversed the increase in NF-kappaB binding in nuclear extracts from TNF-alpha-treated cells. These studies show that inhibition of proteasome-mediated IkappaB degradation results in inhibition of TNF-alpha induced IL-8 production in A549 cells by limiting NF-kappaB-mediated gene transcription.

Cell Line↗
PubMed1997

Clinical implications of ketorolac for postoperative analgesia.

Ketorolac is the only nonsteroidal anti-inflammatory drug (NSAID) in widespread clinical use that is available in an injectable form. Though similar to aspirin and ibuprofen, it is much more potent. In fact, it is potent enough to be useful for postsurgical pain either alone or in combination with other pain relief strategies. For many types of pain, ketorolac is comparable in potency with opioids though the mechanism by which it relieves pain is significantly different. Ketorolac has a much longer duration than morphine or meperidine but has a slower onset. Though we sometimes perceive NSAIDs as almost harmless, ketorolac is a potent drug and, like other potent drugs, has the potential to produce potent adverse effects including organ disfunction and allergic reaction. Risk factors for these adverse effects are well understood, allowing the clinician to plan the ketorolac use safely. Well planned patient selection and ketorolac administration can improve patient care by reducing opioid side effects and improving analgesia while speeding patient recovery and PACU discharge times.

Analgesics, Non-Narcotic↗
PubMed1997

AANA journal course: update for nurse anesthetists-improving the safety of subarachnoid and epidural blocks--Part A.

Hypotension caused by reduced venous return to the heart is a common hazard during subarachnoid and epidural anesthesia. Reduced venous return can also cause severe bradycardia and even cardiac arrest. The infusion of a crystalloid intravenous preload prior to the injection of local anesthetic helps prevent these complications. Unfortunately, intravenous fluid preloading prior to subarachnoid or epidural block is neither appropriate for all patients nor is it always effective. Vasopressor infusions and lower extremity compression, though not completely studied, may allow for further decreases in the incidence of hypotension and bradycardia. When dosing an epidural catheter, making each dose a test dose and observing for signs of subarachnoid or intravascular injection decreases the incidence of hypotension, seizure, and cardiotoxicity. The pathophysiology of cardiac arrest and resuscitation is different during major conduction block due primarily to changes in peripheral vascular tone and venous return to the heart. Neural injury associated with regional anesthesia is due to needle trauma, hematoma, injectate toxicity, ischemia, and compression. Though neural injury is rare, it is more commonly associated with blocks performed in the lumbar region (spinals and epidurals) than in other types of blocks.

Anesthesia, Epidural↗
PubMed1997

AANA Journal course: update for nurse anesthetists--improving the efficacy of subarachnoid and epidural blocks--Part B.

In Part A of this two-part Journal course, issues of safety during subarachnoid and epidural blocks were examined (see the August 1997 issue of the AANA Journal). Part B deals with the effectiveness of spinal and epidural blocks. Although the overall failure rate for subarachnoid and epidural blocks is low, regional anesthesia is not always effective. Knowing the failure rates for various types of regional blocks and the factors that influence the rate of failure is useful for planning anesthetic care and choosing the most effective techniques. Combined spinal and epidural techniques offer the quick onset of a spinal with the continuous dosing and controllability of an epidural. The combined spinal and epidural technique is somewhat more complicated to perform especially in regard to test dosing. Opioids and vasoconstrictors enhance the density and duration of spinal and epidural blocks. In addition, opioids can be used to provide postoperative analgesia after the block has worn off. While opioid induced respiratory depression was a significant hazard during the initial development of spinal and epidural opioid techniques, refinements in dosing and monitoring of these patients have reduced the incidence of this complication to a low level. While alpha agonists, such as epinephrine, do prolong the duration of some types of blocks, they also introduce or exacerbate problems, such as urinary retention, itching, and even hypotension. Whatever technique is used, careful patient selection, allowing adequate time for the block to set up, and administering small doses of a systemic analgesic or sedative if needed may make the difference between the success or failure of a well-performed block.

Anesthesia, Epidural↗
PubMed1996

Inhibition of viral replication reverses respiratory syncytial virus-induced NF-kappaB activation and interleukin-8 gene expression in A549 cells.

Previous studies have demonstrated that respiratory syncytial virus (RSV) infection of airway epithelial cells results in the expression of a number of cytokines, such as interleukin-8 (IL-8), that are transcriptionally regulated by nuclear factor kappaB (NF-kappaB). In the studies reported here, we demonstrate that treatment of RSV-infected A549 cells with 100 microg of ribavirin (a viral replication inhibitor) per ml results in reversal of RSV-induced NF-kappaB activation, IL-8 mRNA expression, and IL-8 protein production in A549 cells. These data confirm that viral replication is a key step in RSV-induced NF-kappaB activation and IL-8 production.

Antiviral Agents↗
PubMed1996

Mechanism of RSV-induced IL-8 gene expression in A549 cells before viral replication.

Previous studies demonstrated that respiratory syncytial virus (RSV) infection of A549 cells induced interleukin (IL)-8 gene expression and protein release from the cells as early as 2 h after treatment [M. A. Fiedler, K. Wernke-Dollries, and J. M. Stark. Am. J. Physiol. 269 (Lung Cell. Mol. Physiol. 13): L865-L872, 1995; J. G. Mastronarde, M. M. Monick, and G. W. Hunninghake. Am. J. Respir. Cell Mol. Biol. 13: 237-244, 1995]. Furthermore, the effects of RSV at the 2-h time point were not dependent on viral replication. The studies reported here were designed to test the hypothesis that active and inactive RSV induce IL-8 gene expression in A549 cells at the 2-h time point by a mechanism dependent on the activation of the nuclear transcription factor NF-kappa B Northern blot analysis indicated that IL-8 gene expression occurred independent of protein synthesis 2 h after A549 cells were treated with RSV. Analysis of nuclear extracts from RSV-treated A549 cells by electrophoretic mobility shift assays demonstrated that NF-kappa B was activated as early as 15 min after RSV was added to the cells and remained activated for at least 90 min. In contrast, baseline levels of NF-IL-6 and activator protein-1 (AP-1) did not change over this period of time. Deoxyribonuclease footprint analysis of a portion of the 5'-flanking region of the IL-8 gene demonstrated two potential regions for transcription factor binding, which corresponded to the potential AP-1 binding site, and potential NF-IL-6 and NF-kappa B binding sites. Mutational analysis of the 200-bp 5'-untranslated region of the IL-8 gene demonstrated that activation of NF-kappa B and NF-IL-6 were required for RSV-induced transcriptional activation of the IL-8 gene.

DNA Mutational Analysis↗