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Biomedical subjects

Hector R Wong

Publications and source records attributed to Hector R Wong.

44 records · Page 3Linked to original sources
PubMed2002

Hyperoxia prolongs tumor necrosis factor-alpha-mediated activation of NF-kappaB: role of IkappaB kinase.

Hyperoxia and tumor necrosis factor-alpha (TNFalpha) are two canonical signals centrally involved in the pathophysiology of acute lung injury. We have attempted to elucidate the effects of these two stimuli on the signal transduction pathways of lung parenchymal cells. In cultured human lung epithelial cells, exposure to hyperoxia alone (95% oxygen) did not affect NF-kappaB activation or degradation of the NF-kappaB inhibitory protein, IkappaB alpha. Stimulation with TNFalpha alone increased NF-kappaB activation within 1 h and induced IkappaB alpha degradation within 0.5 h. After TNFalpha alone, NF-kappaB activation returned to baseline within 2 h and this corresponded with near complete IkappaB alpha resynthesis within 1 h of stimulation. In contrast, simultaneous exposure to hyperoxia and TNFalpha prolonged NF-kappaB activation up to 4 h, and IkappaB alpha degradation up to 2 h after stimulation. Hyperoxia did not affect TNFalpha-mediated resynthesis of IkappaB alpha mRNA. Hyperoxia alone did not induce IkappaB kinase (IKK) activity, but significantly prolonged TNFalpha-mediated activation of IKK activity. Hyperoxia alone did not activate the intercellular adhesion molecule-1 (ICAM-1) promoter, but augmented TNFalpha-mediated activation of the ICAM-1 promoter. These data demonstrate that while hyperoxia alone does not affect activation of NF-kappaB, hyperoxia prolongs TNFalpha-mediated activation of NF-kappaB. The mechanism of this effect involves, in part, prolonged degradation of IkappaB alpha resulting from prolonged activation of IKK.

Cell Line↗
PubMed2002

The stress response decreases NF-kappaB activation in liver of endotoxemic mice.

Recent studies suggest that the stress (heat shock) response protects cells and tissues from inflammatory and other noxious insults. The transcription factor nuclear factor-kappa B (NF-kappaB), normally sequestered in the cytoplasm by its inhibitory protein IkappaB, regulates many genes involved in the inflammatory response to critical illness. Endotoxemia is associated with increased NF-kappaB activity in liver but the effect of the stress response on endotoxin-induced NF-kappaB activation in the liver is not known. We hypothesized that the stress response inhibits NF-kappaB DNA binding activity in liver during endotoxemia. The stress response was induced in mice by hyperthermia (42 degrees C for 3 min) or sodium arsenite (10 mg/kg) and resulted in increased hepatic heat shock protein-72 levels. After induction of the stress response, mice were injected subcutaneously with endotoxin (12.5 mg/kg) or a corresponding volume of sterile saline. NF-kappaB DNA binding activity in the nuclear fraction of liver tissue increased and cytoplasmic IkappaB-alpha levels decreased after endotoxin injection, with a maximal effect seen at 60 min. The endotoxin-induced increase in NF-kappaB DNA binding activity and decrease in IkappaB-alpha levels were inhibited by prior induction of the stress response. In additional experiments, treatment of mice with sodium arsenite after induction of endotoxemia blunted the increase in NF-kappaB activity, indicating a therapeutic potential of sodium arsenite, in addition to its preventive effect. The present results suggest that the protective effects of the stress response in vivo may, at least in part, be due to inhibited NF-kappaB activation.

Animals↗
PubMed2002

Parthenolide, an inhibitor of the nuclear factor-kappaB pathway, ameliorates cardiovascular derangement and outcome in endotoxic shock in rodents.

Parthenolide is a sesquiterpene lactone used in folk medicine for its anti-inflammatory activity. Recent in vitro studies have shown that this compound inhibits the nuclear factor (NF)-kappaB pathway. This study examines the effect of parthenolide in endotoxic shock in rodents. Endotoxic shock was induced by administration of Escherichia coli endotoxin in rats. Three groups of rats received parthenolide (0.25, 0.5, or 1 mg/kg) 15 min before endotoxin; another group received parthenolide (1 mg/kg) 3 h after endotoxin. In vehicle-treated rats, administration of endotoxin caused severe hypotension, which was associated with a marked hyporeactivity to norepinephrine in ex vivo thoracic aortas. Immunohistochemistry showed positive staining for nitrotyrosine, poly(ADP-ribose) synthetase (PARS) and apoptosis, whereas Northern blot analysis showed increased mRNA expression of inducible nitric-oxide synthase (iNOS) in thoracic aortas. Elevated levels of plasma nitrate/nitrite were also found. Elevated lung levels of myeloperoxidase activity were indicative of infiltration of neutrophils. These inflammatory events were preceded by cytosolic degradation of inhibitor kappaBalpha (IkappaBalpha) and activation of nuclear NF-kappaB in the lung. In vivo pretreatment and post-treatment with parthenolide improved the hemodynamic profile and reduced plasma nitrate/nitrite and lung neutrophil infiltration in a dose-dependent fashion. Vascular hyporeactivity of ex vivo aortas was ameliorated. Treatment with parthenolide also abolished nitrotyrosine formation, PARS expression, and apoptosis and reduced iNOS mRNA content in thoracic aortas. DNA binding of NF-kappaB was inhibited by parthenolide in the lung, whereas degradation of IkappaBalpha was unchanged. In a separate set of experiments, pretreatment or post-treatment with parthenolide significantly improved survival in mice challenged with endotoxin. We conclude that parthenolide exerts beneficial effects during endotoxic shock through inhibition of NF-kappaB.

Animals↗
PubMed2002

Proteasome inhibitors induce heat shock response and increase IL-6 expression in human intestinal epithelial cells.

In previous studies, the heat shock response, induced by hyperthermia or sodium arsenite, increased interleukin (IL)-6 production in intestinal mucosa and cultured human enterocytes. A novel way to induce the heat shock response, documented in other cell types, is treatment with proteasome inhibitors. It is not known if proteasome inhibition induces heat shock in enterocytes or influences IL-6 production. Here we tested the hypothesis that treatment of cultured Caco-2 cells, a human intestinal epithelial cell line, with proteasome inhibitors induces the heat shock response and stimulates IL-6 production. Treatment of Caco-2 cells with one of the proteasome inhibitors MG-132 or lactacystin activated the transcription factor heat shock factors (HSF)-1 and -2 and upregulated cellular levels of the 72-kDa heat shock protein HSP-72. The same treatment resulted in increased gene and protein expression of IL-6, a response that was blocked by quercetin. Additional experiments revealed that the IL-6 gene promoter contains a HSF-responsive element and that the IL-6 gene may be regulated by the heat shock response. The present results suggest that proteasome inhibition induces heat shock response and IL-6 production in enterocytes and that IL-6 may be a heat shock-responsive gene, at least under certain circumstances. The observations are important considering the multiple biological roles of IL-6, both locally in the gut mucosa and systemically, and considering recent proposals in the literature to use proteasome inhibitors in the clinical setting to induce the heat shock response.

Acetylcysteine↗
PubMed2002

Interactions between the heat shock response and the nuclear factor-kappa B signaling pathway.

The heat shock response (HSR) and the nuclear factor (NF)-kappa B signaling pathway are two fundamental cellular responses. Various laboratories have documented in vitro and in vivo interactions between the HSR and NF-kappa B activation when they are activated sequentially. For example, induction of the HSR before a proinflammatory signal inhibits NF-kappa B activation and NF-kappa B-dependent proinflammatory gene expression. The central point of control appears to be at the level of I kappa B alpha phosphorylation as demonstrated by HSR-mediated inhibition of I kappa B kinase activation and HSR-mediated induction of intracellular phosphatase activity. In addition, induction of the HSR can independently increase de novo expression of the I kappa B alpha gene, thereby providing another potential mechanism through which the HSR can modulate cellular proinflammatory signaling. Another level of interaction is illustrated by the observation that various pharmacologic inhibitors of the NF-kappa B pathway are capable of simultaneously inducing the HSR. In direct contrast, induction of the HSR after a proinflammatory signal can lead to programmed cell death. Further understanding of how these two fundamental cellular responses interact at the molecular level holds the potential to elucidate some of the molecular interactions that occur during disease states common to critical care medicine.

Animals↗
PubMed2002

The A2A receptor mediates an endogenous regulatory pathway of cytokine expression in THP-1 cells.

Adenosine is an endogenous nucleoside that regulates numerous cellular functions including inflammation. Adenosine acts via cell-surface receptors subtyped as A1, A2A, A2B, and A3. The A2A receptor (A2AR) has been linked to anti-inflammatory effects of adenosine. Furthermore, microarray analysis revealed increased A2AR mRNA in lipopolysaccharide (LPS)-stimulated monocytes. We hypothesized that endogenous adenosine inhibited LPS-mediated tumor necrosis factor (TNF) production via A2AR stimulation. Using THP-1 cells, our results demonstrated that LPS increased expression of cellular A2AR and adenosine. A2AR agonism with 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine (CGS 21680) after LPS decreased TNF production in a dose- and time-dependent manner, whereas A2AR antagonism significantly increased TNF and blocked the inhibitory effect of CGS 21680. This inhibitory pathway involved A2AR stimulation of cyclic adenosine monophosphate (cAMP) to activate protein kinase A, resulting in phosphorylation of cAMP response element-binding protein (CREB). Phospho-CREB had been shown to inhibit nuclear factor-kappaB transcriptional activity, as was observed with CGS 21680 treatment. Thus, following immune activation with LPS, endogenous adenosine mediates a negative feedback pathway to modulate cytokine expression in THP-1 cells.

Adenosine↗
PubMedDate not supplied

Epigallocatechin, a green tea polyphenol, attenuates myocardial ischemia reperfusion injury in rats.

Epigallocatechin-3-gallate (EGCG) is the most prominent catechin in green tea. EGCG has been shown to modulate numerous molecular targets in the setting of inflammation and cancer. These molecular targets have also been demonstrated to be important participants in reperfusion injury, hence this study examines the effects of EGCG in myocardial reperfusion injury. Male Wistar rats were subjected to myocardial ischemia (30 min) and reperfusion (up to 2 h). Rats were treated with EGCG (10 mg/kg intravenously) or with vehicle at the end of the ischemia period followed by a continuous infusion (EGCG 10 mg/kg/h) during the reperfusion period. In vehicle-treated rats, extensive myocardial injury was associated with tissue neutrophil infiltration as evaluated by myeloperoxidase activity, and elevated levels of plasma creatine phosphokinase. Vehicle-treated rats also demonstrated increased plasma levels of interleukin-6. These events were associated with cytosol degradation of inhibitor kappaB-alpha, activation of IkappaB kinase, phosphorylation of c-Jun, and subsequent activation of nuclear factor-kappaB and activator protein-1 in the infarcted heart. In vivo treatment with EGCG reduced myocardial damage and myeloperoxidase activity. Plasma IL-6 and creatine phosphokinase levels were decreased after EGCG administration. This beneficial effect of EGCG was associated with reduction of nuclear factor-kB and activator protein-1 DNA binding. The results of this study suggest that EGCG is beneficial for the treatment of reperfusion-induced myocardial damage by inhibition of the NF-kappaB and AP-1 pathway.

Animals↗