The role of apoptosis in systemic lupus erythematosus.
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Apoptosis↗
Biomedical subjects
M Salmon
Publications and source records attributed to M Salmon.
Postgraduate degrees for rheumatology trainees: an options appraisal of MD, PhD and MSc degrees. On behalf of the BSR Research and Training Committee.
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Education, Graduate↗
Cysteinyl-leukotrienes partly mediate eotaxin-induced bronchial hyperresponsiveness and eosinophilia in IL-5 transgenic mice.
Eotaxin, a selective chemoattractant for eosinophils, induces lung eosinophilia and bronchial hyperresponsiveness (BHR) when administered intratracheally to interleukin-5 (IL-5) transgenic mice. We determined whether these effects of eotaxin were mediated through the production of cysteinyl-leukotrienes. IL-5 transgenic mice were administered eotaxin (5 micrograms) intratracheally after pretreatment with either diluent or a selective 5-lipoxygenase inhibitor SB210661 or a cysteinyl-leukotriene receptor antagonist, pranlukast. Twenty-four hours later, bronchial responsiveness to acetylcholine was measured and the degree of eosinophil influx was determined in bronchoalveolar lavage fluid (BALF) or in lung tissue. Both pranlukast and SB210661 significantly attenuated BHR induced by eotaxin with logPC(50), which is the concentration of acetylcholine needed to increase baseline insufflation pressure by 50%, from -0.43 +/- 0.16 to 0.39 +/- 0.10 and from -0.22 +/- 0.10 to 0.53 +/- 0.10, respectively (p < 0.05). There was also a significant attenuation of the eosinophil counts in BALF and in airways. BALF levels of leukotriene C(4) (LTC(4)) showed a significant increase after eotaxin from 23.9 +/- 6.7 to 165.0 +/- 35.0 pg/ml (p < 0.05) but were partially suppressed by both SB210661 (71.2 +/- 21.0) and pranlukast (62.7 +/- 11.5). Concentrations of LTB(4) were not significantly changed. We conclude that eotaxin-induced effects in the airways of IL-5 transgenic mice are partly mediated by the activation of 5-lipoxygenase enzyme leading to the generation of cysteinyl-leukotrienes.
Acetylcholine↗
Contribution of bradykinin B(1) and B(2) receptors in allergen-induced bronchial hyperresponsiveness.
Bradykinin (BK) is a peptide mediator generated at sites of inflammation and its effects are mediated through constitutively expressed B(2) receptor or through induction of B(1) receptors. We examined the role of these receptors in bronchial hyperresponsiveness (BHR). Brown-Norway rats sensitized with ovalbumin (OA) and Al(OH)(3) intraperitoneally, were exposed 3 wk later to either saline or OA aerosol. B(1) receptor antagonist desArg(10)[Hoe140] (200 nmol/kg or 1 micromol/kg, intraperitoneally) or B(2) receptor antagonist Hoe140 (200 nmol/kg, intraperitoneally) was administered 30 min before allergen exposure. Hoe140 had no effect on OA-induced BHR to acetylcholine (ACh) and bronchoalveolar lavage fluid (BALF) cellular profiles, but inhibited bronchoconstriction to BK (p < 0.04). At both doses, desArg(10)[Hoe140] dose-dependently inhibited allergen-induced BHR to ACh (p < 0.01), but had no effect on bronchoconstriction to BK or baseline ACh responsiveness. The inflammatory cells in BALF were not affected apart from reduced lymphocyte numbers at the highest dose. B(1) receptor mRNA expression measured by Northern analysis was increased after allergen exposure in sensitized lungs, with a peak at 2 to 6 h after exposure, whereas B(2) receptor mRNA expression remained unchanged. Newly induced BK B(1) receptors may be involved in allergen-induced BHR to ACh, whereas constitutive B(2) receptors mediate BK-induced bronchoconstriction.
Acetylcholine↗
alpha4 integrin-dependent eotaxin induction of bronchial hyperresponsiveness and eosinophil migration in interleukin-5 transgenic mice.
We investigated the roles of eosinophil infiltration and activation induced by the eosinophil-selective chemokine eotaxin, and of the expression of eosinophil alpha4 and beta2 integrins in causing bronchial hyperresponsiveness (BHR) in interleukin (IL)-5 CBA/Ca transgenic mice. These mice did not show BHR, despite the presence of some eosinophils in the lungs. Intratracheal mouse recombinant eotaxin (3 micrograms) did not induce BHR in wild-type mice. In IL-5 transgenic mice, eotaxin (3 and 5 micrograms) increased responsiveness at 24 h and increased eosinophils in bronchoalveolar lavage (BAL) fluid by 9.4- and 14-fold by 24 h, respectively, together with augmentation of eosinophil peroxidase activity and eosinophil infiltration in the airway submucosa. Using flow cytometry, the expression of alpha4, CD11b, and CD18 was upregulated in BAL, but not in blood, eosinophils. A rat anti-alpha4 antibody inhibited eotaxin-induced BHR and eosinophil migration and activation, but an anti-CD11b antibody had no significant effects on BHR. A combination of both antibodies was more effective. IL-5 and eotaxin synergize in the induction of BHR and airway eosinophilia, effects that are dependent on the induction of eosinophil alpha4 integrin. Expression of BHR depends on the recruitment and activation of eosinophils.
Animals↗
Homophilic PECAM-1(CD31) interactions prevent endothelial cell apoptosis but do not support cell spreading or migration.
PECAM-1 (CD31) is a highly abundant cell surface glycoprotein expressed on haemopoietic and endothelial cells. As well as mediating homophilic (PECAM-1/PECAM-1) adhesion, PECAM-1 can also bind the integrin alphavbeta3. Both PECAM-1 and alphavbeta3 have been shown to have roles in regulating angiogenesis, endothelial tube formation and in the case of alphavbeta3, endothelial cell apoptosis. In this study we show that despite being expressed at equivalent levels, endothelial alphavbeta3 is not a ligand for PECAM-1. Rather, PECAM-1 supports homophilic binding on HUVEC with similar characteristics to those we have previously reported for leukocytes and becomes tyrosine phosphorylated after homophilic PECAM-1 and integrin/fibronectin engagement. Immunoprecipitation studies show that in addition to SHP-2, tyrosine phosphorylated PECAM-1 can interact with at least four other phosphoproteins in pervanadate stimulated HUVEC. While PECAM-1/PECAM-1 interactions support robust endothelial cell adhesion, they do not support cell spreading or migration. In addition PECAM-1 homophilic adhesion rescues HUVEC from serum deprivation-induced apoptosis. Taken together our results indicate that PECAM-1 homophilic interactions play an important role in interendothelial cell adhesion, survival and signalling.
Apoptosis↗
SB 203580, an inhibitor of p38 mitogen-activated protein kinase, enhances constitutive apoptosis of cytokine-deprived human eosinophils.
The role of p38 mitogen-activated protein (MAP) kinase, and extracellular-regulated protein kinase -1 and -2 in regulating constitutive apoptosis and interleukin (IL)-5-induced survival of human eosinophils have been investigated. Two populations of donors were identified whose eosinophils, in the absence of exogenous cytokines, underwent apoptosis at different rates. Eosinophils were thus arbitrarily classified as either "fast"- or "slow"-dying cells, where greater or less than 15% of the cells were apoptotic at 2 days, respectively. The selective p38 MAP kinase inhibitor, SB 203580, increased constitutive eosinophil apoptosis in both populations (EC(50) approximately 2 microM) as evinced from morphological analysis, flow cytometry, and DNA laddering. The ability of SB 203580 to kill eosinophils was not due to nonspecific toxicity or through the inhibition of prostanoid or leukotriene production. Exposure of eosinophils to IL-5, at a concentration (10 pM) that enhanced survival maximally, abolished SB 203580-induced apoptosis. In contrast PD 098059, which selectively blocks MAP kinase kinase (MEK) 1, did not affect apoptosis of fast- or slow-dying eosinophils, or the enhanced survival of cells effected by IL-5. Collectively, these results suggest that: 1) the basal activity of p38 MAP kinase may regulate the survival of cytokine-deprived eosinophils through inhibition of apoptosis, 2) the enhancement of eosinophil survival effected by IL-5 is mediated by a mechanism(s) divorced from the activation of p38 MAP kinase, and 3) neither spontaneous eosinophil apoptosis nor their enhanced survival by IL-5 involves the activation of MEK-1.
Apoptosis↗
Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection.
Interferon-gamma receptor ligand-binding chain (IFN-gammaR1) or signaling chain (IFN-gammaR2) deficiency, like interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency, predispose to severe infections due to poorly virulent mycobacteria and salmonella. A child with bacille Calmette-Guérin and Salmonella enteritidis infection was investigated. Mutations in the genes for IFN-gammaR1, IFN-gammaR2, IL-12Rbeta1, and other molecules implicated in IL-12- or IFN-gamma-mediated immunity were sought. A large homozygous deletion within the IL-12 p40 subunit gene was found, precluding expression of functional IL-12 p70 cytokine by activated dendritic cells and phagocytes. As a result, IFN-gamma production by lymphocytes was markedly impaired. This is the first discovered human disease resulting from a cytokine gene defect. It suggests that IL-12 is essential to and appears specific for protective immunity to intracellular bacteria such as mycobacteria and salmonella.
BCG Vaccine↗
IL-7-dependent extrathymic expansion of CD45RA+ T cells enables preservation of a naive repertoire.
We have investigated the regulation of adult and cord blood CD45RA+ T cell proliferation and apoptosis to identify factors that may control the naive T cell pool. Cord CD45RA+ T cells were highly susceptible to spontaneous apoptosis as compared with CD45RA+ T cells from adults. Apoptosis was prevented by the addition of IL-2, IL-4, IL-7, and IL-15 which signal via the gamma-chain of the IL-2 receptor. IL-7 prevented the decrease in Bcl-2 and Bcl-xL and induced cell cycling in up to 20% of cord T cells after 8 days, resulting in a threefold increase in cord T cell numbers. However, the expanded cells retained a CD45RA+ CD45RO- phenotype. Similar results were obtained with adult CD45RA+ T cells. IL-7-expanded CD45RA+ RO- T cells expressed CD45RO after stimulation through the TCR. Investigations into the regulation of replicative senescence showed that after 12 days in culture with IL-7, cord blood CD45RA+ T cell proliferation resulted in telomere shortening. Nevertheless, IL-7-expanded cord blood T cells still maintained longer telomeres than unstimulated adult T cells. IL-7 but not IL-2 could directly induce high telomerase activity which probably retarded the rate of telomere shortening in cord blood T cells. These results suggest that proliferation induced by IL-7 may be important for extrathymic expansion of neonatal CD45RA+ T cells and may also contribute to the maintenance of the adult CD45RA+ T cell pool.
Adult↗
The role of apoptosis in the resolution of T cell-mediated cutaneous inflammation.
We have investigated cutaneous purified protein derivative-induced delayed-type hypersensitivity (DTH) responses in healthy volunteers to determine features associated with both the generation and resolution of the reaction. The clinical peak of the response occurred at day 3; however, T cell numbers were maximal on day 7. There was a preferential increase of CD4+ CD45RO+ T cells on day 7, which was largely due to proliferation, since a mean of 19% was in cycle. The proliferation of this subset was associated with the presence of IL-15, which was expressed as early as 12 h, and IL-2, which showed peak expression at 7 days. By day 14, there was a significant decrease in both the mean T cell number/unit area and IL-2 and IL-15 expression in perivascular infiltrates. Maximal CD95 (Fas/Apo-1) ligand and TNF-alpha expression were observed at 7 days and were associated with the presence of 1.83% (range 0.81-2.48%) apoptotic T cells. At 14 days, CD95 ligand and TNF-alpha expression were reduced significantly, and the presence of 2.5% (range 1.5-3.75%) of apoptotic T cells at this time was probably due to cytokine deprivation, associated with decreased Bcl-2 relative to Bax expression. The induction and resolution of the Mantoux reaction may depend on the expression of cytokines, such as IL-2 and IL-15, which regulate both proliferation and apoptosis in T cells. Failure to control either of these phases of the Mantoux reaction may contribute to the chronicity of inflammatory responses in certain cutaneous diseases.
Adult↗
Hatchling sea turtles use surface waves to establish a magnetic compass direction
Hatchling sea turtles emerge from underground nests, crawl to the ocean, and swim away from the land. In shallow water near shore, hatchlings maintain offshore headings by swimming into oceanic waves; in deeper water, however, turtles appear to rely on different mechanisms to maintain their courses. To determine whether loggerhead hatchlings, Caretta caretta L., are able to transfer a course initiated on the basis of waves to a course maintained by a magnetic compass, we studied the orientation behaviour of turtles that had been exposed to waves for either 15 or 30 min before being tested in still water. Hatchlings that swam into waves for 15 min failed to continue swimming on similar courses when the waves were discontinued, but turtles that swam into waves for 30 min maintained similar mean headings after the waves stopped. Inverting the vertical component of the magnetic field during the test period reversed the direction of orientation of this latter group of turtles. Thus, hatchlings can transfer a heading induced by waves to a magnetic compass, and thereby continue to migrate away from land after contact with the coast is lost. Migratory orientation in turtles resembles that of birds in that both rely on multiple cues and an ability to transfer information between various cues and compasses at appropriate times during the journey.Copyright 1998 The Association for the Study of Animal Behaviour.
Journal Article↗
Proliferation of airway epithelium after ozone exposure: effect of apocynin and dexamethasone.
Ozone is an environmental pollutant with potent oxidizing properties. We investigated whether exposure to ozone-induced cell proliferation in the lungs of rats, and determined the effect of an antioxidant and of a glucocorticosteroid in Brown-Norway (BN) rats. Following single ozone exposure (0.5, 1.0, or 3.0 ppm for 6 h), proliferating cell nuclear antigen (PCNA) expression, as determined with immunohistochemistry, was significantly increased in the bronchial epithelium and alveolar epithelium as compared with controls exposed to filtered air with a maximal effect at 24 to 48 h (p < 0.001). Apocynin (5 mg/kg, orally), a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, reduced the PCNA index in bronchial epithelium induced by ozone (3 ppm, 6 h) from 11.5 +/- 1.3% (percent of nuclear cells expressing PCNA) to 4.4 +/- 1.3% (mean +/- SEM; p < 0.05). Dexamethasone (3 mg/kg, intraperitoneally) also reduced the PCNA index in bronchial epithelium, from 19.2 +/- 2.3% to 10.9 +/- 2.6% (p < 0.05). Dexamethasone but not apocynin inhibited ozone-induced neutrophil influx. Rats exposed repeatedly to ozone (3.0 ppm, 3 h, on three occasions 48 h apart) expressed a lower PCNA index in bronchial epithelium than did rats exposed only once at 1.9 +/- 0.7% versus 6.0 +/- 0.9%, respectively (p < 0.05). The proliferative epithelial response following a single exposure to ozone is modulated through oxidative and inflammatory mechanisms probably involving neutrophils.
Acetophenones↗
Setting a national informatics agenda for nursing education and practice to prepare nurses to develop and use information technology.
Efforts to build a telecommunications infrastructure that will link people nationally and internationally includes a focus on health care. A telecommunications infrastructure will add value to providers and consumers of health care only if they are able to use it to access and share information. Nurses often have information technology available to them, but are inadequately prepared to use it. Under the direction of the National Advisory Council for Nursing Education and Practice (NACNEP), the Division of Nursing convened a panel of experts in nursing informatics to recommend an informatics agenda. Using a nominal group technique the informatics experts identified informatics needs and recommended initiatives that would better prepare nurses to use and develop information technology. Their recommendations were reviewed by NACNEP resulting in a national informatics agenda for nursing education and practice.
Computer User Training↗
Co-occurrence of AIDS and tuberculosis: results of a database "match" and investigation.
PURPOSE: To conduct a match between the AIDS and Tuberculosis (TB) Registries in Philadelphia. METHODS: Database extracts for the year 1993 were prepared manually and matched by name, birth date, and social security number. Reported cases not matching with those on the primary registry were investigated. Proportion levels of comorbidity were calculated. Predictors of comorbidity were evaluated separately for the TB sample and for the AIDS sample. RESULTS: The proportion of comorbid patients with AIDS alive at midyear was 4.7%; 17.1% of TB cases were also HIV-positive. Twenty-three percent of AIDS cases were falsely reported as having active TB; the false-positive rate in TB Control for HIV seropositivity was 4.2%. Having public or no health insurance, injection drug use (IDU) or heterosexual risk background (HET), and being nonwhite and female were significant predictors of active TB in persons with AIDS. CONCLUSIONS: A registries' data match can provide useful information and result in improved validity for both registries. Although women with AIDS initially appeared to have a higher risk of having active TB, additional parallel analyses suggested that this effect was primarily the result of the 1993 expansion of the definition of AIDS.
Acquired Immunodeficiency Syndrome↗
Upregulation of intracellular glutathione by fibroblast-derived factor(s): enhanced survival of activated T cells in the presence of low Bcl-2.
Activated interleukin-2 (IL-2)-dependent T cells express high levels of Bcl-2 protein. On cytokine withdrawal, Bcl-2 expression decreases and the cells die rapidly by apoptosis. We have previously shown that the survival of IL-2-deprived T cells can be promoted by factor(s) secreted by fibroblasts. Here we report that reduced glutathione (GSH), but not its oxidized counterpart GSSG, also enhances the in vitro survival of these cells. Exogenous GSH mediates its effect intracellularly, as (1) endogenous glutathione concentrations are increased up to fivefold in the presence of GSH, and (2) acivicin, an inhibitor of transmembrane GSH transport, abrogates GSH-dependent survival. The GSH-rescued T cells do not proliferate and express only low levels of Bcl-2, resembling W138 fibroblast-rescued T cells. We, therefore, investigated a role for GSH in fibroblast-promoted T-cell survival. We show that W138-promoted survival results in elevated GSH levels in surviving T cells and is abrogated by buthionine sulfoximine (BSO), an inhibitor of GSH synthesis. Furthermore, both W138-promoted T-cell survival and GSH upregulation are associated with large molecular weight molecules (>30 kD). Thus, the upregulation of GSH by W138 fibroblasts appears to be crucial in their ability to enhance the survival of cytokine-deprived activated T cells in vitro.
Apoptosis↗
Inhibition of T cell apoptosis in the rheumatoid synovium.
Synovial T cells in rheumatoid arthritis are highly differentiated and express a phenotype suggesting susceptibility to apoptosis (CD45RB dull, CD45RO bright, Bcl-2 low, Bax high, Fas high). However, no evidence of T cell apoptosis was found in synovial fluid from any of 28 patients studied. In contrast, synovial fluid from 10 patients with crystal arthritis showed substantial levels of T cell apoptosis. The failre of apoptosis was not an intrinsic property of rheumatoid synovial T cells, as they showed rapid spontaneous apoptosis on removal from the joint. Synovial T cells from rheumatoid arthritis and gout patients could be rescued from spontaneous apoptosis in vitro either by IL-2R gamma chain signaling cytokines (which upregulate Bcl-2 and Bcl-XL) or by interaction with synovial fibroblasts (which upregulates Bcl-xL but not Bcl-2). The phenotype of rheumatoid synovial T cells ex vivo (Bcl-2 low, Bcl-xL high) suggested a fibroblast-mediated mechanism in vivo. This was confirmed by in vitro culture of synovial T cells with fibroblasts which maintained the Bcl-xL high Bcl-2 low phenotype. Synovial T cells from gout patients were Bcl-2 low Bcl-xL low and showed clear evidence of apoptosis in vivo. Inhibition experiments suggested that an integrin-ligand interaction incorporating the Arg-Gly-Asp motif is involved in fibroblast-mediated synovial T cell survival. We propose that environmental blockade of cell death resulting from interaction with stromal cells is a major factor in the persistent T cell infiltration of chronically inflamed rheumatoid synovium.
Apoptosis↗
Cellular environments and apoptosis: tissue microenvironments control activated T-cell death.
Activated T cells must be removed by apoptosis at the end of an immune response in order to maintain cellular homeostasis. Although recent attention has focused on the role of CD95 (Fas/APO-1) in the elimination of activated T cells, apoptosis can also be induced by cytokine deprivation. Here, Arne Akbar and Mike Salmon describe how both death pathways interact in activated T cells and are profoundly influenced by different tissue microenvironments.
Animals↗
Inducible nitric oxide synthase after sensitization and allergen challenge of Brown Norway rat lung.
1. We studied the effects of ovalbumin (OA) sensitization and challenge on inducible nitric oxide synthase (iNOS) gene and protein expression in Brown-Norway rats in vivo. 2. By use of Northern analysis, a 4.4-kb iNOS mRNA transcript was weakly observed in control rat lung but there was a 3 fold increase in lungs sensitized to OA alone (P<0.05). In sensitized rats, four hours after exposure to OA aerosol, there was a 6 fold increase in iNOS mRNA transcript (P<0.05), which returned to baseline at 24 h. 3. Immunostaining with an anti-mouse iNOS antibody revealed some patchy staining of airway epithelium in naive rats. There were no changes in sensitized rats exposed to saline, but sensitized and OA-exposed rats showed increased expression in iNOS staining in macrophages. 4. Electrophoretic mobility shift assays of lung nuclear extracts showed a marked increase in nuclear factor-kappaB (NF-kappaB)-binding activity at 2 h after allergen exposure with return to baseline at 6, 12 and 24 h. 5. We concluded that there is increased iNOS gene and protein expression associated with increased NF-kappaB DNA-binding in lungs of sensitized and challenged rats. The increase in iNOS expression may underlie the increase in exhaled NO found after allergen challenge and may contribute to the development of allergen-induced airway hyperresponsiveness.
Allergens↗