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M P O'Donnell

Publications and source records attributed to M P O'Donnell.

At least 19 recordsLinked to original sources
PubMed2001

Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure.

BACKGROUND: The pathophysiologic and potential therapeutic role of selectins in renal ischemia-reperfusion injury (IRI) is not fully understood, due in part to redundancy in the roles of individual selectins. We hypothesized that blockade of ligands for all three selectins using a novel small molecule (TBC-1269) would improve the course of renal IRI by overcoming redundancy issues. This was investigated in a rat model of renal IRI. METHODS: Rats were treated with TBC-1269 either during or post-IRI. The effects of TBC-1269 were investigated in two models of renal IRI: moderate IRI (30 minutes bilateral renal artery clamping) and severe IRI (45 minutes clamping). The combination of anti-E- and anti-P-selectin antibodies also was investigated in rats subjected to moderate IRI. Renal function, histological injury and mortality were assessed. RESULTS: Rats treated with TBC-1269 during moderate IRI showed significantly reduced serum creatinine (SCr) and tubular necrosis post-ischemia compared to control animals. By contrast, delayed treatment (post-IRI) did not show a reduction in SCr. In rats with severe IRI, TBC-1269 treatment during IRI significantly reduced mortality at 48 hours post-ischemia. Rats with moderate IRI and treated with the combination of anti-E- and anti-P-selectin antibodies showed significantly reduced SCr compared to control rats at 24 hours post-ischemia. CONCLUSIONS: Small molecule selectin ligand inhibition provides a novel and effective approach to attenuate ischemic acute renal failure. Timing of treatment is crucial to success.

Acute Kidney Injury↗
PubMed2001

Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure.

Leukocytes have been implicated in the pathogenesis of ischemic acute renal failure (ARF), but the roles of the individual cell types involved are largely unknown. Recent indirect evidence suggests that T cells may play an important role in a murine model of ARF. In the current study, we found that mice deficient in T cells (nu/nu mice) are both functionally and structurally protected from postischemic renal injury. Reconstitution of nu/nu mice with wild-type T cells restored postischemic injury. We then analyzed the contribution of the individual T cell subsets to postischemic injury and found that mice deficient in CD4(+) T cells, but not mice deficient in CD8(+) T cells, were significantly protected from ARF. Direct evidence for a pathophysiologic role of the CD4(+) T cell was obtained when reconstitution of CD4-deficient mice with wild-type CD4(+) T cells restored postischemic injury. In addition, adoptive transfers of CD4(+) T cells lacking either the costimulatory molecule CD28 or the ability to produce IFN-gamma were inadequate to restore injury phenotype. These results demonstrate that the CD4(+) T cell is an important mediator of ischemic ARF, and targeting this cell may yield novel therapies.

Acute Kidney Injury↗
PubMed2000

Low-density lipoprotein-induced expression of interleukin-6, a marker of human mesangial cell inflammation: effects of oxidation and modulation by lovastatin.

Low-density lipoprotein (LDL) may contribute to the pathogenesis of glomerulosclerosis by stimulating a mesangial cell inflammatory response. Interleukin-6 (IL-6) is a marker of active inflammation and ongoing glomerular injury. Therefore, we investigated the effects of native and oxidized LDL on human mesangial cell production of IL-6 and a possible modulation of this inflammatory response by lovastatin, which has been shown to ameliorate experimental glomerulosclerosis. Human mesangial cells were exposed for 6 or 24 h to culture medium containing either native LDL alone or a LDL mixture containing 5 or 20% oxidized LDL. We found that native LDL stimulated 6 h mRNA expression and secretion of IL-6. This effect was further enhanced, in a dose-related manner, when mesangial cells were exposed to increasing concentrations of oxidized LDL. Lovastatin markedly inhibited mesangial cell expression of IL-6 mRNA and reduced IL-6 secretion. The inhibitory effects of lovastatin were overridden at least partially by exogenous mevalonate. We conclude that LDL, and particularly oxidized LDL, might contribute to the pathogenesis of glomerular disease by modulating the inflammatory response of human mesangial cells, as assessed by the stimulation of IL-6 expression. Moreover, this inflammatory response can be prevented by lovastatin, providing a potential direct anti-inflammatory mechanism by which HMG-CoA reductase inhibitors may attenuate lipid-induced glomerular injury.

Base Sequence↗
PubMed2000

Renal tubulointerstitial fibrosis. New thoughts on its development and progression.

Current investigation of the pathogenesis of tubulointerstitial injury indicates that both interstitial fibroblasts and renal tubular epithelial cells promote extracellular matrix accumulation. Moreover, two peptides--TGF-beta and angiotensin II--produced locally or delivered in the circulation, appear to play a central role in renal fibrosis. Pharmacologic amelioration of renal fibrosis may require methods directed at multiple factors involved in the fibrotic process, including angiotensin II, TGF-beta, and the proliferation and activation of interstitial fibroblasts.

Angiotensin II↗
PubMed1999

The central role of nuclear factor-kappa B in mesangial cell activation.

BACKGROUND: Nuclear factor-kappa B (NF-kappa B) is a family of transcription factors that is recognized by the kappa B enhancer element. Numerous proinflammatory genes have binding sites for NF-kappa B, and the products of these genes are an integral part of cellular activation and inflammatory response systems. Because there is a close relationship between NF-kappa B and mediators of cell activation, it is possible that a disruption of NF-kappa B-activating pathways may effectively influence mesangial cell activation. METHODS: We reviewed available studies related to both NF-kappa B and mesangial cells in order to provide evidence for the role of NF-kappa B in mesangial cell activation. RESULTS: Studies reported by this laboratory and others showed that various experimental maneuvers that modulate NF-kappa B activation result in a parallel modulation of proinflammatory molecule production in cultured mesangial cells. Likewise, the ability of the inhibitors of NF-kappa B activation to down-regulate the inflammatory response in animal models of renal disease has been recently demonstrated. CONCLUSIONS: These data suggest a pivotal role of NF-kappa B in mesangial cell activation and designate it as an obvious target for the modulation of this activation. Studies are necessary to characterize the role of NF-kappa B in human renal injury.

Animals↗
PubMed1999

Effects of lovastatin on expression of cell cycle regulatory proteins in vascular smooth muscle cells.

BACKGROUND: The sequential appearance of cyclins D and E is thought to initiate subsequent DNA synthesis in proliferating cells. Previous studies have reported that DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs) was suppressed by the HMG-CoA reductase inhibitor lovastatin. The effects of lovastatin on cell cycle regulatory proteins in proliferating VSMCs, however, are largely unknown. Thus, we investigated the sequential expression of cyclin D1, cyclin E, cyclin-dependent kinase (CDK) 4, CDK2, and p27Kip1 in cultured rat VSMCs stimulated by platelet-derived growth factor (PDGF)-BB in the presence or absence of lovastatin. METHODS: Quiescent VSMCs, with and without lovastatin (20 microM) pretreatment for nine hours, were stimulated by PDGF-BB (25 ng/ml). The incorporation of tritiated thymidine was done to assess DNA synthesis. VSMC lysates were obtained every 6 hours for up to 36 hours after stimulation and were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis using relevant polyclonal antibodies. Autoradiograms were analyzed using a densitometer. RESULTS: The peak expression of cyclins D1 and E occurred at 18 and 30 hours of PDGF stimulation, respectively. Concomitant expression of CDK4 and CDK2 was also observed. The expression of p27Kip1, by contrast, was reduced in association with DNA synthesis. Lovastatin suppressed DNA synthesis and reduced the expression of cyclin D1 and cyclin E, whereas p27Kip1 expression was strongly induced by lovastatin pretreatment. CDK4 and CDK2 expression was unaffected by lovastatin treatment. CONCLUSIONS: PDGF-BB induces cyclins D1 and E prior to the onset of DNA synthesis in VSMCs. Lovastatin may suppress DNA synthesis in VSMCs by inducing p27Kip1 and reducing expression of cyclins D1 and E.

Animals↗
PubMed1999

Importance of geranylgeranyl pyrophosphate for mesangial cell DNA synthesis.

BACKGROUND: Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are isoprenoid products of the intracellular mevalonate pathway used for prenylation of several low molecular weight G proteins, including Ras. It is likely that platelet-derived growth factor (PDGF) stimulation of mesangial cell proliferation requires prenylated, low molecular weight G proteins. The purpose of this study was to investigate the dependence of platelet-derived growth factor-stimulated mesangial cell DNA synthesis and cell membrane Ras incorporation on FPP and GGPP. METHODS: Quiescent human mesangial cells were exposed to PDGF (25 ng/ml) to stimulate DNA synthesis. Some cells were also treated with the HMG-CoA reductase inhibitor lovastatin (2.5 to 10.0 microM), which inhibits isoprenoid synthesis, in the presence or absence of exogenous FPP or GGPP. DNA synthesis was assessed by thymidine incorporation, and Western blot analysis was used to measure total cell membrane Ras. RESULTS: Stimulation of mesangial cells with PDGF did not increase total cell membrane Ras. Lovastatin reduced cell membrane Ras, and this was prevented by simultaneous exposure of mesangial cells to exogenous FPP (2.5 to 10.0 microM) or GGPP (1 to 5 microM). Lovastatin also reduced PDGF-stimulated mesangial cell DNA synthesis by 90%, and this was completely prevented by simultaneous exposure of cells to exogenous GGPP (1 microM), but not to FPP. CONCLUSIONS: The results of this study suggest that both FPP and GGPP can provide for mesangial cell membrane Ras localization and that PDGF-stimulated mesangial cell DNA synthesis requires the isoprenoid GGPP.

Blotting, Western↗
PubMed1999

Lipophilic statins induce apoptosis of human vascular smooth muscle cells.

BACKGROUND: The accumulation of vascular smooth muscle cells (VSMC) in the intima is an early feature of atherosclerosis that results from a balance of migration from the media, proliferation, and eventual death (including programmed cell death) of VSMC. Several reports have described that HMG-CoA reductase inhibitors (statins) attenuate both the migration and proliferation of VSMC. However, the potential effect of statins on VSMC programmed cell death has received little attention. METHODS: Human and rat VSMC were incubated with different concentration of statins in the presence of fetal bovine serum as a survival factor. The presence of apoptosis was evaluated by morphological criteria, flow cytometry and DNA electrophoresis. RESULTS: Lipophilic statins induced, in a dose-dependent manner the appearance of VSMC apoptosis. The effect of statins was fully reversed by mevalonate, farnesylpyrophosphate, and geranylgeranypyrophosphate, but not by cholesterol or other mevalonate metabolites, suggesting a role for isoprenoids in VSMC apoptosis. In addition, the induction of apoptosis by statins was associated with the inhibition of prenylation of Rho B. CONCLUSIONS: The present results suggest that protein prenylation inhibition by statins may be involved in statin-induced VSMC apoptosis. These data provide a new potential mechanism by which statins may modulate the evolution of atherosclerotic lesions.

Animals↗
PubMed1998

Gas leak and gastric insufflation during controlled ventilation: face mask versus laryngeal mask airway.

PURPOSE: To compare two airway management techniques, face mask (FM) with oropharyngeal airway and laryngeal mask airway (LMA), with respect to the effectiveness of positive pressure ventilation and airway maintenance. METHODS: After induction of anaesthesia, two airway management techniques (FM or LMA) and three peak pressures (20, 25 and 30 cm H2O) were randomly applied during controlled ventilation in 60 patients. Data collected included inspiratory and expiratory volumes and presence of gastro-oesophageal insufflation. Leak was calculated by subtracting the expiratory from the inspiratory volume, expressed as a fraction of the inspiratory volume. RESULTS: Expiratory volumes (mean +/- SD) at 20, 25 and 30 cm H2O for LMA ventilation were 893 +/- 260, 986 +/- 276 and 1006 +/- 262 respectively, and for FM ventilation 964 +/- 264, 1100 +/- 268 and 1116 +/- 261. Leak fractions at 20, 25 and 30 cm H2O for LMA ventilation were 0.21 +/- 0.15, 0.24 +/- 0.18 and 0.26 +/- 0.18 respectively, and for FM ventilation 0.14 +/- 0.09, 0.14 +/- 0.09 and 0.12 +/- 0.08. The frequency of gastro-oesophageal insufflation was 1.6%, 5% and 5% for the LMA and 5%, 15% and 26.6% for the FM for ventilation pressures of 20, 25 and 30 cm H2O respectively which was greater with LMA use. CONCLUSION: Ventilation was adequate in all patients using both techniques. Leak was pressure dependent and greater with LMA use. Most of the leak was vented to the atmosphere via the pharynx. Gastro-oesophageal insufflation was more frequent with ventilation using the face mask. LMA use with positive pressure ventilation would appear to be a better airway management method than the face mask.

Adult↗
PubMed1998

Renal cell cytokine production stimulates HIV-1 expression in chronically HIV-1-infected monocytes.

Renal infiltration of human immunodeficiency virus type 1 (HIV-1)-infected monocytes might play an important role in the development of HIV-associated nephropathy (HIVAN). In the present study, we investigated the effects of cytokines produced by cultured human mesangial cells (HMC) and proximal tubular epithelial cells (PTEC) on HIV-1 expression in chronically HIV-1-infected promonocytes (U1 cells). Human mesangial cells constitutively secreted interleukin-6 (IL-6) but not tumor necrosis factor-alpha (TNF-alpha) into the culture medium, whereas PTEC constitutively secreted both IL-6 and TNF-alpha. Coculture of U1 cells with HMC or PTEC for 72 hours markedly stimulated HIV-1 expression, with the p24 antigen concentration in the coculture supernatants ranging from approximately 200 to 1850 pg/ml. The presence of anti-IL-6 antibody in the coculture medium nearly completely blocked HIV-1 expression in the HMC/U1 cell cocultures (P < 0.05). Anti-IL-6 antibody and anti-TNF-alpha antibody blocked HIV-1 expression in the PTEC/U1 cell cocultures by 40% and 53%, respectively (P < 0.05). Moreover, the combination of anti-IL-6 and anti-TNF-alpha antibodies additively reduced coculture HIV-1 expression by 87% (P < 0.05). We conclude that renal cell production of IL-6 and TNF-alpha might provide a potent stimulus for HIV-1 expression in HIV-1-infected monocytes that infiltrate the kidney, and that this may play an important role in the pathogenesis of HIVAN.

AIDS-Associated Nephropathy↗
PubMed1998

Lovastatin reduces glomerular macrophage influx and expression of monocyte chemoattractant protein-1 mRNA in nephrotic rats.

Glomerular expression of monocyte chemoattractant protein-1 (MCP-1) and subsequent glomerular macrophage infiltration may play an important role in the development of glomerulosclerosis. Previous studies have shown that lovastatin ameliorates experimental renal disease and reduces MCP-1 expression in serum-stimulated, cultured mesangial cells. We investigated the effects of lovastatin on glomerular MCP-1 expression and macrophage infiltration in rats with puromycin aminonucleoside (PA) nephrosis, an experimental model of renal disease characterized by early macrophage infiltration. Male Sprague-Dawley rats were pretreated for 5 days with either lovastatin (4 mg/kg) or vehicle. At the end of pretreatment, the lovastatin-pretreated rats received a single i.v. injection of PA (50 mg/kg) and continued to receive daily lovastatin thereafter. The vehicle-pretreated rats received i.v. injections of either PA or saline, and continued to receive daily vehicle treatment thereafter. Ten days after PA injection, the vehicle-treated PA rats showed increased (P < 0.05) serum cholesterol (359 +/- 25 mg/100 mL) and urine albumin excretion (343 +/- 95 mg/24 hr), compared with the vehicle-treated control rats (61 +/- 3 mg/100 mL and 2.5 +/- 0.6 mg/24 hr, respectively). Serum cholesterol (193 +/- 22 mg/dL) and urine albumin excretion (255 +/- 68 mg/24 hr) were less in the lovastatin-treated PA rats than in the vehicle-treated PA rats. The number of glomerular macrophages, assessed as ED-1-positive cells, per glomerular profile was increased 77% in the vehicle-treated PA rats (3.3 +/- 0.2) compared with the vehicle-treated control rats (1.8 +/- 0.2) (P < 0.05). By contrast, the number of glomerular macrophages was not elevated in the lovastatin-treated PA rats (2.3 +/- 0.2). Thus, lovastatin in vivo can attenuate glomerular macrophage infiltration. This may represent one mechanism by which lovastatin ameliorates experimental glomerular disease.

Animals↗
PubMed1997

Irbesartan lowers blood pressure and ameliorates renal injury in experimental non-insulin-dependent diabetes mellitus.

In the present study, we investigated the effects of the angiotensin (Ang) II receptor antagonist, irbesartan, on blood pressure and renal structural injury in obese Zucker rats (OZR), an experimental model of non-insulin-dependent diabetes mellitus (NIDDM). Twenty-six-week-old OZR with established renal disease were administered either low-dose (15 mg/kg) or high-dose (50 mg/kg) irbesartan in the drinking water for a period of 18 weeks. Irbesartan caused dose-related reductions in blood pressure, and reduced by 47 to 60% the percent of glomeruli with sclerosis at 44 weeks of age (P < 0.05). In addition, irbesartan at the higher dose reduced the tubulointerstitial injury score at 44 weeks by approximately 75% (P < 0.05). By contrast, irbesartan did not significantly reduce albuminuria in OZR. The results of the present study demonstrate that the Ang II receptor antagonist irbesartan can reduce blood pressure and ameliorate glomerular and tubulointerstitial injury in an experimental model of NIDDM.

Albuminuria↗
PubMed1996

Patient-controlled analgesia versus patient-controlled analgesia plus continuous infusion after hip replacement surgery.

OBJECTIVE: To compare the efficacy and adverse effect profile of patient-controlled analgesia (PCA) versus PCA plus continuous infusion (PCACI) after hip replacement surgery. DESIGN: Prospective, randomized, open pilot study. SETTING: Large teaching institution. PARTICIPANTS: Thirty-four patients undergoing hip replacement or revision of hip replacement surgery. INTERVENTIONS: Patients were randomized to receive PCA morphine: 1 mg with 6-minute lockout, or PCACI, using the same dose, with a 0.5-1 mg/h continuous infusion. Pain intensity, sedation, narcotic use, injection/attempt ratio (I/A), and adverse effects were assessed. RESULTS: No significant differences in pain intensity were identified. Morphine use was not different between groups: PCA 61.8 +/- 35.0 and PCACI 74.2 +/- 54.9 mg (p =0.394). A trend toward an increased 12-hour I/A ratio was evident in the PCACI group: PCA 0.73 +/- 0.18 and PCACI 0.86 +/- 0.17 (p =0.073). Patient-reported adverse effects, sedation, and inability to sleep secondary to pain occurred similarly. Eight of 18 PCACI patients required discontinuation of either the continuous infusion mode or of PCA therapy entirely secondary to adverse effects. CONCLUSIONS: When compared with PCA therapy, PCACI was not associated with improved pain control and more patients receiving PCACI required discontinuation of therapy secondary to adverse effects.

Aged↗