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Biomedical subjects

C J Kelly

Publications and source records attributed to C J Kelly.

At least 55 records · Page 3Linked to original sources
PubMed1998

Thermotolerance induces heat shock protein 72 expression and protects against ischaemia-reperfusion-induced lung injury.

BACKGROUND: Ischaemia-reperfusion injury is mediated by neutrophil-endothelial interaction. Induction of heat shock proteins attenuates neutrophil-endothelial interactions. The aim of this study was to determine whether thermal preconditioning could have a protective effect on neutrophil-mediated lung injury in an animal model of lower torso ischaemia-reperfusion. METHODS: Sprague-Dawley rats were randomized into: control, ischaemia-reperfusion, and ischaemia-reperfusion preconditioned with hyperthermia groups. Ischaemia-reperfusion injury was induced by infrarenal aortic clamping for 30 min and reperfusion for 120 min. Thermotolerance was induced by raising the core body temperature to 40.5-41.5 degrees C for 15 min, 18 h before ischaemia-reperfusion. Wet:dry lung (W:D) weight ratio, bronchoalveolar lavage protein (BALprot) concentration, tissue myeloperoxidase (MPO) activity and bronchoalveolar lavage polymorphonuclear neutrophil (BAL PMN) count were measured. Heat shock protein 72 (hsp72) expression in lung, intestine and mesentery was measured using Western immunoblotting. RESULTS: Ischaemia-reperfusion resulted in a significant increase in tissue oedema (W:D weight ratio) and BALprot concentration. In addition there was a marked increase in tissue neutrophil infiltration (MPO activity, BAL PMN concentration). Preconditioning with hyperthermia resulted in increased expression of hsp72 and significantly reduced tissue oedema and neutrophil infiltration. CONCLUSION: Thermal preconditioning protects against neutrophil-mediated ischaemia-reperfusion-induced lung injury, possibly by increasing the expression of heat shock proteins.

Animals↗
PubMed1998

Ocular manifestations of pediatric disease.

A review of the ocular manifestations of pediatric disease is in some ways a review of pediatrics itself. A paper this size cannot hope to be comprehensive in scope or encyclopedic in detail. Instead, we have chosen to touch on recent developments in pediatrics that we feel may be of particular interest to the ophthalmologist, as well as certain areas of pediatric ophthalmology that make it clear that a child's ocular disease takes place in the larger context of the growing child.

Arthritis, Juvenile↗
PubMed1998

TGF-beta and regulation of interstitial nephritis.

TGF-beta1 has been implicated as a profibrotic growth factor in the bulk of published experimental work regarding the actions of this cytokine in kidney disease. Such investigations have spanned a methodologic spectrum from in vivo analyses to cell culture work with purified growth factors and analyses of gene expression. Important correlative work using clinical specimens has established the presence of augmented TGF-beta expression in renal diseases characterized by excessive sclerosis or fibrosis. While in the aggregate this information supports a compelling argument in favor of TGF-beta having a predominant effect to accelerate progressive renal failure, the cytokine clearly also demonstrates effects which would tend to abrogate renal injury. We provide a summary of published and new experimental data outlining immunosuppressive and 'renal-protective' actions of TGF-beta1.

Animals↗
PubMed1998

Transient 5-oxoprolinuria (pyroglutamic aciduria) with systemic acidosis in an adult receiving antibiotic therapy.

5-Oxoprolinuria is a recognized condition with increased urinary excretion of 5-oxoproline and is associated with a variety of inborn metabolic defects involving the series of enzyme-linked reactions known as the gamma-glutamyl cycle. We report the unusual case of a 35-year-old woman who initially presented with staphylococcal pneumonia but went on to develop a transient high anion gap metabolic acidosis. The development and subsequent complete recovery from this acidosis were subsequently shown to be related in time to the intravenous administration of the antibiotics flucloxacillin and netilmicin. Analysis of the patient's urine for organic acids revealed massively increased excretions of 5-oxoproline at the peak of her acidosis. We suggest that this patient developed a transient disturbance in the gamma-glutamyl cycle involving the 5-oxoprolinase step, which resulted in accumulation of 5-oxoproline that caused a severe high anion gap metabolic acidosis. The administered antibiotics remain as possible causative agents.

Acidosis↗
PubMed1997

Inhibition of inducible nitric oxide synthase intensifies injury and functional deterioration in autoimmune interstitial nephritis.

T lymphocytes are exquisitely sensitive to the antiproliferative effects of nitric oxide. We examined the effects of oral administration of two nitric oxide synthase inhibitors, Nw-nitro-L-arginine methyl ester (L-NAME) and L-N6-(1-iminoethyl)lysine (L-NIL), on the course of T cell-dependent autoimmune interstitial nephritis in Brown Norway rats. Kidneys from rats immunized to produce interstitial nephritis display a net generation of nitric oxide end products. By immunohistochemical staining, the cytokine-inducible nitric oxide synthase (iNOS) is expressed in cortical tubular epithelial cells. Treatment with either inhibitor results in markedly more severe disease following immunization. Animals receiving L-NAME were hypertensive, while those treated with L-NIL, a highly selective inhibitor of iNOS, were not. Evaluation of the expression of IFN-gamma, IL-2, and IL-4 in diseased kidneys by quantitative reverse transcriptase-PCR demonstrated that L-NAME-treated animals displayed significantly augmented levels of IFN-gamma and IL-2 with preserved ratios of IFN-gamma/IL-4 and IL-2/IL-4, while L-NIL-treated animals had augmented levels of IL-2 and IFN-gamma with augmented IFN-gamma/IL-4 and IL-2/IL-4 ratios. Animals treated with L-NAME or L-NIL both had augmented Ag-specific IgG responses. The L-NAME group demonstrated increases in both the IgG2a and IgG1 subtypes, with a constant IgG2a/IgG1 ratio, while the L-NIL group demonstrated an increase in the ratio of the IgG2a/IgG1 response. These Ab and cytokine data suggest that the L-NIL-treated animals had a skewing of their immune response toward a Th1-like response. We conclude that in autoimmune interstitial nephritis, generation of nitric oxide through the iNOS pathway has host-protective effects, and suggest that this may be broadly applicable to T cell-mediated pathologies.

Administration, Oral↗
PubMed1997

Nephritogenic T cells use granzyme C as a cytotoxic mediator.

Cytoplasmic granules of cytotoxic T lymphocytes contain several proteins that may be involved in cell-mediated cytotoxicity. We have previously described nephritogenic T cell clones that are cytotoxic to cultured renal proximal tubular epithelial cells (MCT). One of these clones, M52.34.1, expresses perforin, a cytotoxic mediator. We investigated the expression of other granule-associated proteases of M52.34.1. Granzymes A and B have been extensively studied in T cell-mediated cytotoxicity, and associated with tissue destruction in models of transplantation. However, the activity of other granzymes has not been as extensively investigated. We focused our studies on granzyme C. Northern blots showed very high levels of granzymes B and C mRNA expression in M52.34.1 cells 3 days following T cell activation. There was no expression of granzyme A mRNA. An antisense oligonucleotide made from the 5'-upstream region of the murine granzyme C exon 1 inhibited granzyme C mRNA expression in M52.34.1 when added at a concentration of 50 microM to the culture medium for 2 days. There was no inhibition of granzyme C mRNA expression with the sense oligonucleotide. The granzyme C antisense oligonucleotide inhibited M52.34.1 cytotoxicity to MCT at effector:target ratios of 20:1 and 40:1. M52.34.1 cells mediate inflammatory interstitial nephritis following adoptive transfer. If T cells were resuspended in 200 microM of the antisense oligonucleotide prior to subcapsular transfer, the recipient kidneys showed markedly diminished tubular cell destruction, suggesting that granzyme C can also be an important mediator of cytotoxicity in vivo.

Animals↗
PubMed1997

Nitric oxide and the immunomodulation of experimental allergic encephalomyelitis.

Previous studies examining the effect of nitric oxide synthase (NOS) inhibition on the course of experimental allergic encephalomyelitis (EAE) have yielded conflicting results. This may relate to the use of nonspecific inhibitors and to differences between active and adoptive EAE. We examined the effect of treatment with L-N-(1-iminoethyl)lysine (L-NIL), a selective inhibitor of the cytokine-inducible isoform of NOS, on the clinical course of active and adoptive EAE in Lewis rats. We find that while L-NIL treatment of recipients is protective in adoptive EAE, treatment of active EAE with L-NIL leads to a marked accentuation of disease expression. In L-NIL-treated animals treated with myelin basic protein/complete Freund's adjuvant (MBP/CFA), disease onset is accelerated and clinical symptoms are more severe. Accentuation of integrated disease scores is seen even if L-NIL treatment is started 5 days following immunization. The histological findings in involved spinal cords from L-NIL-treated animals with active EAE are similar to those from untreated animals with similar clinical scores. L-NIL treatment of MBP/CFA-immunized animals does not prevent recovery from clinical symptoms, nor does it allow for reinduction of disease in animals previously immunized with MBP/CFA. Treatment of F344 rats, a strain which is relatively nonsusceptible for EAE, with L-NIL results in consistent evidence of EAE following immunization with MBP/CFA. These findings, together with our previous work on interstitial nephritis, support a role for endogenously generated NO in immunoregulation of T cell responses following immunization with antigen in CFA, and suggest that inducibility of NOS expression may be an important susceptibility factor for autoimmunity.

Adjuvants, Immunologic↗
PubMed1997

Differential effects of lower limb revascularisation on organ injury and the role of the amino acid taurine.

Lower torso revascularisation following ischaemia results in a systemic inflammatory response. Endothelial barrier function is disrupted by neutrophil-derived proteases and oxidants. Taurine, an amino acid found in large quantities in neutrophils, is a powerful endogeneous anti-oxidant. The aims of this study were to investigate the systemic effects of reperfusion following lower limb revascularisation and to evaluate the role of taurine administration in preventing this injury. A rat model of aortic occlusion (30 min) followed by 2 h of reperfusion was used. Animals were randomised to one of three groups (n = 10 per group): control; ischaemia reperfusion untreated (IR) and taurine-treated. Taurine (4% solution) was administrated orally for 48 h prior to the experiment. Neutrophil infiltration and microvascular permeability were assessed by measuring tissue myeloperoxidase activity and wet/dry weights respectively in lung, liver, kidney, and in cardiac and skeletal muscle. Statistical analysis was by means of analysis of variance (ANOVA). Reperfusion resulted in pulmonary and renal microvascular injury as assessed by organ oedema. Hepatic tissue, skeletal and cardiac muscle were unaffected by lower limb revascularisation. Taurine was effective in preventing neutrophil-mediated pulmonary but not renal microvascular injury. These data suggest that, whilst reperfusion-induced pulmonary injury is predominantly neutrophil-mediated, agents other than neutrophil-derived oxidative metabolites, capable of independently causing organ injury through direct endothelial damage, are produced during reperfusion.

Animals↗
PubMed1997

Plasma factors augment neutrophil and endothelial cell activation during aortic surgery.

Lung injury following reperfusion results from endothelial damage caused by release of cytotoxic products by activated neutrophils (PMN) in the pulmonary microvasculature. This process is facilitated by the release of pro-inflammatory cytokines and arachidonic metabolites following the outset of reperfusion. This study aimed to evaluate the effect of plasma obtained before and after revascularisation on neutrophil and endothelial cell activation. Plasma (IR-plasma) was obtained from venous blood samples taken before and during aortic cross-clamping, and 5, 40 and 60 min following clamp removal in seven patients undergoing elective infrarenal aortic aneurysm resection. PMN from healthy volunteers (n = 5) were incubated with these plasma samples or with fMLP (N-formylmethionyl-leucyl-phenylalanine) as positive control for 30 min and assessed flow-cytometrically for CD11b expression. Human endothelial cells (ECV-304) were incubated with IR plasma for 2, 4 and 6 h or with tumour necrosis factor (TNF) (20 ng/ml) as positive control and assessed for ICAM-1 expression. Incubation with IR plasma resulted in a significant increase from pre-clamp in PMN CD11b expression. A similar trend was seen in endothelial cell ICAM-1 expression following 2 h incubation. These results indicate that reperfusion-induced endothelial dysfunction may be mediated by plasma factors released upon revascularisation which facilitate neutrophil-endothelial interaction through up-regulation of adhesion receptor expression.

Analysis of Variance↗
PubMed1997

Ruptured abdominal aortic aneurysm--can treatment costs and outcomes be predicted by using clinical or physiological parameters?

Mortality rates for patients undergoing surgery for ruptured abdominal aortic aneurysm (RAAA) remain high. The high cost of providing care for these patients mandates that proposed treatment protocols be evaluated for their cost-effectiveness. This study assessed costs related to outcome in different groups of patients with RAAA. From July 1987 to December 1993, 140 patients underwent emergency surgery for RAAA. Complete data on preoperative haemodynamic status, blood transfusion requirements, intensive care unit (ICU) stay and other hospital costs was available for 94 patients. Seventy-seven males (mean age 71.6(6)) and 17 females (mean age 77.2(6)) underwent surgery. Known risk factors including age (< or > 70 years), shock on admission (systolic blood pressure (BP) < or > 90 mm Hg), sex, and acute renal failure were analysed. For the purpose of comparison, costs (Pounds) were assessed by the ESRI (Economic and Social Research Institute of Ireland) based on 1992 prices. The overall survival rate was 48%: 53% among males and 24% among females (p < 0.05, Chi-squared test). In addition to having a significantly worse outcome than males, female patients with RAAA also had longer hospital and ICU stays and this was reflected in significantly greater expenditure. Similarly, male patients > 70 years old presenting with haemodynamic instability had significantly longer hospital and ICU stays than younger male patients. The average cost per RAAA survival (12,945 Pounds) in this series is not prohibitive, and the greater cost in high risk groups should not discourage intervention.

Acute Kidney Injury↗
PubMed1997

Oral feeding of renal tubular antigen abrogates interstitial nephritis and renal failure in Brown Norway rats.

We have examined whether oral feeding of antigen can regulate the expression of autoimmune interstitial nephritis induced by antigen-in-adjuvant (RTA/CFA) immunization of Brown Norway rats. Male rats were divided into six experimental groups: Group I, RTA/CFA immunization alone; Groups II, III, and IV were pretreated with 1 mg (Group II), 5 mg (Group III), and 25 mg (Group IV) of oral tubular antigen every other day for ten days, followed by RTA/CFA immunization; Group V was pretreated with a control antigen, followed by RTA/CFA immunization; and Group VI was immunized with CFA alone. Renal histology, inulin clearance, DTH responses to RTA, and IgG antibody responses to RTA were monitored as endpoints of the study. Our results demonstrated that Group III and IV animals had significantly less severe renal injury, as assessed by inulin clearance and extent of renal cortical involvement by mononuclear cells. Group II and IV animals had suppressed DTH responses, and only Group IV animals had significantly depressed antigen-specific IgG serum titers. Group III animals had neither suppressed DTH responses or IgG titers. We conclude that oral administration of tubular antigen can modulate the intensity of interstitial nephritis produced by immunization, but that the regulatory mechanism is not dependent (at all doses of fed antigen) on suppressed DTH reactivity to RTA or suppressed antigen-specific IgG.

Administration, Oral↗
PubMed1997

Nitric oxide attenuates interleukin 2-induced lung injury.

BACKGROUND: The pathogenesis of interleukin (IL) 2-induced vascular leak syndrome may be related to neutrophil-mediated endothelial injury. Nitric oxide inhibits neutrophil superoxide anion synthesis and adherence to endothelial cells. The role of systemic nitric oxide in preventing IL-2-induced lung injury was studied in an experimental model. METHODS: Sprague-Dawley rats (seven per group) were randomized to control, IL-2 treatment (1 x 10(6) units), and IL-2 with sodium nitroprusside 0.2 mg/kg. Lung injury was measured by estimation of extravascular lung water (wet:dry weight) and bronchoalveolar lavage (BAL) protein concentration, and by histological findings. Neutrophil infiltration was evaluated by measuring myeloperoxidase activity and BAL neutrophil concentration. RESULTS: IL-2 produced significant lung damage characterized by leucocyte sequestration (increased myeloperoxidase and BAL neutrophil concentrations), pulmonary congestion and microvascular protein leakage (increased wet:dry weight ratio and BAL protein concentration). This injury was reduced significantly by the addition of sodium nitroprusside, the nitric oxide donor. CONCLUSION: Nitric oxide reduces IL-2-induced lung injury.

Animals↗
PubMed1996

Thermotolerance attenuates ischemia-reperfusion induced renal injury and increased expression of ICAM-1.

Thermotolerance describes the process in which hyperthermia induces a transient resistance of the stressed cells to subsequent episodes of oxidative stress. The aims of this study were first, to assess the effect of ischemia-reperfusion (IR) injury on renal function and the expression of the ICAM-1 receptor and MHC antigens, and second, to evaluate the protective effects of thermotolerance on IR induced renal injury and its potential for decreasing allograft rejection, by decreasing alloantigen expression. Sprague-Dawley rats were randomized into three groups: control, IR, and hyperthermia + IR (HIR) (n=8 per group). Thermotolerance was induced 18 hr prior to IR by increasing the core body temperature to 41 degrees C+/-0.5 degrees C for 15 min. After left uninephrectomy, IR was induced by clamping the right renal pedicle for 45 min, followed by 2 hr reperfusion. Myeloperoxidase (MPO) activity was used as an indicator of renal neutrophil influx. Kidney edema was assessed using the weight difference between left and right kidneys. Renal function was evaluated by measuring serum creatinine and urea 2 hr following clamp removal. Immunocytochemistry was used to measure expression of ICAM-1 and MHC antigen. Renal function was significantly impaired by IR with serum creatinine and urea levels of 131.5+/-5.01 microM and 11.2+/-0.71 mM, respectively, compared with controls of 67.9+/-5.11 microM and 8.1+/-0.36 mM, P<0.005 in both cases. Renal function was preserved in the HIR group, serum creatinine (84.8+/-8.58 microM) and urea (9.0+/-0.52 mM) were comparable to that of controls. Renal endothelium was activated in the IR group compared with controls, with increased ICAM-1, and tubular epithelium showed increased class II MHC expression. This up-regulation was prevented by prior induction of thermotolerance. Endothelial permeability was increased in the IR group with MPO activity of 0.8+/-0.08 units/g tissue--twice that of control levels P<0.05--and a marked increase in organ edema. Thermotolerance preserved endothelial barrier function. Thermotolerance may prevent IR injury by preventing endothelium activation and has the potential to modify allograft rejection by decreasing expression of ICAM-1, an important T cell receptor, and class II MHC.

Acclimatization↗
PubMed1996

Loss of high affinity transforming growth factor-beta 1 (TGF-beta 1) binding to a nephritogenic T cell results in absence of growth inhibition by TGF-beta 1 and augmented nephritogenicity.

Transforming growth factor-beta (TGF-beta) affects cellular proliferation and differentiation and has been linked to the development of pathologic extracellular matrix production characteristic of progressive renal disease. TGF-beta 1 is conventionally regarded as having growth-inhibitory activity on T lymphocytes. The growth-regulatory activity of TGF-beta 1 depends on the interaction of TGF-beta 1 with its receptors, especially the type I and II receptors. In this study, we describe a CD4+ nephritogenic T cell clone that, unlike a sister clone with an identical TCR Ag receptor, is not growth inhibited by TGF-beta 1, nor is its nephritogenicity affected by exogenous TGF-beta 1. Although this TGF-beta-resistant T cell clone expresses both type I and II TGF-beta receptors on the cell surface, the affinity of this interaction is markedly diminished compared with that of the sister T cell clone, which does undergo growth arrest in response to extracellular TGF-beta 1. The resistant T cell clone expresses one mutant allele for the type I TGF-beta receptor. This mutation consists of a leucine to glutamine substitution at codon 122, a conserved amino acid in the transmembrane domain. We speculate that this mutation alters the interaction between the type I and II TGF-beta receptors following recognition of ligand by the type II receptor.

Amino Acid Sequence↗
PubMed1996

Glyceryl trinitrate prevents neutrophil activation but not thromboxane release following ischaemia-reperfusion injury.

The aim of this study was to determine whether glyceryl trinitrate (GTN) has a protective effect on neutrophil-mediated lung injury in a model of aortic occlusion (30 min) and reperfusion (120 min). Sprague-Dawley rats were randomized into control (n = 11), ischaemia-reperfusion (IR) (n = 12), and IR treated with GTN (2 micrograms kg-1 min-1) during reperfusion (n = 10). Myeloperoxidase (MPO) activity measured pulmonary neutrophil influx. Pulmonary endothelial permeability was measured by wet:dry weight ratio, bronchoalveolar lavage (BAL) protein and neutrophil counts. Neutrophil superoxide release was measured by flow cytometry in a further IR versus GTN experiment (n = 6 in each group). The significant increase in MPO activity produced by IR to a level of 7.99 units g-1 was prevented by GTN which reduced the level to 4.73 units g-1. The increase in pulmonary microvascular leakage after reperfusion was also prevented by GTN: BAL protein without GTN was 992 micrograms ml-1 and with GTN 579 micrograms ml-1; BAL neutrophil count without GTN was 3219 cells mm-3 and with GTN 820 cells mm-3; the wet:dry lung weight ratio without GTN was 3.8 and with GTN 3.3. Neutrophil superoxide release increased significantly after 40 min of reperfusion in the untreated IR group (P < 0.05). This increase was prevented in the GTN-treated group. GTN administration had no effect on plasma thromboxane production during revascularization. These data suggest that GTN administration during the reperfusion phase has the potential to decrease pulmonary microvascular injury.

Animals↗