Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.59 (MIP)
 4,906 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-10 (IL-10) can downregulate expression of several proinflammatory cytokines including chemokines. This study investigated the role of IL-10 in the acute response of the rat lung to quartz particles. Intratracheal instillation of rats with 1 mg of quartz produced an inflammatory and cytotoxic response demonstrated by increased bronchoalveolar lavage (BAL) fluid neutrophils, lactate dehydrogenase, and protein. IL-10 was detected in rat lung, but IL-10 levels were not altered by quartz. In contrast, quartz increased lung levels of the chemokine macrophage inflammatory protein-2 (MIP-2). Treatment with recombinant murine IL-10 (rmIL-10) attenuated quartz-induced pulmonary inflammation and injury. Pretreatment with anti-IL-10 antiserum enhanced inflammatory responses to quartz. Consistent with effects on quartz-induced inflammation, rmIL-10 and anti-IL-10 serum decreased and increased, respectively, lung MIP-2 mRNA and protein in response to quartz. Additionally, rmIL-10 reduced production of hydrogen peroxide, superoxide anion, and nitric oxide by BAL cells from quartz-exposed and control rats. These results demonstrate that IL-10 is expressed in rat lung and downregulates quartz-induced inflammation and cell activation. The mechanism of the anti-inflammatory action of IL-10 after quartz administration involves, at least in part, attenuation of MIP-2 expression.
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PMID:Interleukin-10 regulates quartz-induced pulmonary inflammation in rats. 981 5

Transition metals are components of airborne particles and have been implicated in adverse health effects. The relative inflammatory potential of these metals is usually inferred from separate studies that focus on only one or a few individual metals. Comparisons of relative potency among several metals from these separate studies can be difficult. In one comprehensive study, we measured the pulmonary effects of equimolar doses of six metals in soluble form. Our purpose was to compare inflammatory potential and pulmonary toxicity among individual transition metals. Rats received saline, 0.1 or 1.0 micromol/kg of vanadium, nickel, iron(II), copper, manganese, or zinc as sulfates. Bronchoalveolar lavage (BAL) was performed at 0, 4, 16, or 48 h postinstillation. All treatments except V showed increased lactate dehydrogenase activity in BAL fluid; Cu- and Ni-exposed animals had the highest levels. Protein levels in BAL fluid were more than five times higher in Cu-exposed animals compared to other metal treatments at 16 and 48 h. At the 0.1 micromol/kg dose, only Cu induced significant neutrophilia at 16 and 48 h. For the 1.0 micromol/kg dose, all metals tested induced significant neutrophilia, with mean neutrophil numbers for Cu and Mn significantly higher compared to the other metals. At 48 h, neutrophil numbers were still elevated in all metal exposures. Only Mn caused substantial eosinophilia. At the 1.0 micromol/kg dose, only Cu induced macrophage inflammatory protein-2 (MIP-2) mRNA at 4 h. By 48 h, induction of MIP-2 mRNA was observed for all metal exposures except Cu, which subsequently returned to baseline levels. On an equimolar basis, Cu was the most proinflammatory metal, followed by Mn and Ni, while V, Fe(II), and Zn induced similar levels of inflammation. Overall, there were many similarities in the pulmonary responses of the metals we tested. However, we also observed divergent, metal-specific responses. These differential responses suggest that metals induce pulmonary inflammation by differing pathways or combinations of signals.
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PMID:Differential ability of transition metals to induce pulmonary inflammation. 1170 99

Chemotherapy and radiotherapy are performed for cancer patients with the hope that dying cancer cells are safely scavenged by phagocytic cells such as macrophages. In this study, we examined cytokine production by macrophages during and after the phagocytosis of etoposide-treated P388 cells in vitro and in vivo. Etoposide caused apoptosis as early as 5 h after treatment, as assessed as to the exposure of phosphatidylserine, increase in membrane permeability and DNA ladder formation. Phagocytosis by phorbol myristate acetate (PMA)-treated THP-1 cells occurred marginally when P388 cells were treated with etoposide for 10 h, while it occurred significantly with P388 cells treated for 24 h, as evidenced by flow cytometry and confocal microscopy. PMA-treated THP-1 cells produced pro-inflammatory cytokines, such as interleukin (IL)-1alpha, IL-8 and macrophage migration inhibitory factor (MIF), but not anti-inflammatory cytokines among those tested at the mRNA level during and after the phagocytosis of apoptotic cells. IL-8 and MIF were also produced at the protein level, and the IL-8 production was dependent on cell-to-cell contact when the plasma membranes of apoptotic cells were intact enough not to leak one of the cytoplasmic enzymes, lactate dehydrogenase. In addition, etoposide-treated P388 cells induced neutrophil infiltration as well as MIP-2 production upon injection into the peritoneal cavity of either normal mice or mice with sterile peritonitis. When macrophages ingesting and/or binding apoptotic P388 cells were isolated from the mice with sterile peritonitis using a cell sorter, they were found to produce MIP-2 upon culture.
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PMID:Cytokine production by macrophages in association with phagocytosis of etoposide-treated P388 cells in vitro and in vivo. 1175 16

Heat shock protein 70 (HSP70) mediates delayed cardioprotection of preconditioning. Cytosolic calcium ([Ca(2+)])(i) overload precipitates injury, whereas attenuation of [Ca(2+)](i) overload is believed to be responsible for cardioprotection. There is evidence suggesting a link between HSP70 and [Ca(2+)](i) homeostasis. We hypothesize that activation of HSP70 by preconditioning may restore [Ca(2+)](i) homeostasis altered by ischemic insults. To test the hypothesis, we determined the effects of preconditioning with metabolic inhibition or pretreating with U50,488H [trans-(+)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide (a kappa-opioid receptor agonist)] on viability and injury, HSP70 expression, and [Ca(2+)](i) in ventricular myocytes subjected to metabolic inhibition and anoxia (MI/A), with blockade of HSP70 synthesis. In myocytes with vehicle pretreatment, the percentage of dead cells determined by trypan blue exclusion, the injury reflected by release of lactate dehydrogenase, and the resting [Ca(2+)](i) measured by spectrofluorometry significantly increased, whereas the amplitude of electrically induced [Ca(2+)](i) transient decreased, after 10 min with 10 mM 2-deoxy-d-glucose and 10 mM sodium dithionite, known to cause MI/A. However, when myocytes were subjected for 30 min to either 20 mM lactate and 10 mM 2-deoxy-d-glucose (MIP) or 30 microM U50,488H (UP) 20 h before MI/A, the changes in viability and injury, and [Ca(2+)](i) responses were significantly attenuated. These were accompanied by a significantly increased HSP70 expression. Furthermore, blockade of HSP70 synthesis with selective antisense oligonucleotides abolished the beneficial effects of MIP or UP. This study provides first evidence that activation of HSP70 induced by preconditioning, which conferred delayed cardioprotection, restored partially the [Ca(2+)](i) homeostasis altered by ischemic insults.
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PMID:Effects of heat shock protein 70 activation by metabolic inhibition preconditioning or kappa-opioid receptor stimulation on Ca2+ homeostasis in rat ventricular myocytes subjected to ischemic insults. 1505 1

Inhalation of crystalline silica can produce lung inflammation and fibrosis. Inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) is believed to be involved in silica-induced lung disease. To investigate the role of iNOS-derived NO in this disease, the responses of iNOS knockout (KO) versus C57Bl/6J wild-type (WT) mice to silica were compared. Male mice (8-10 wk old, mean body weight 24.0 g) were anesthetized and exposed, by aspiration, to silica (40 mg/kg) or saline. At 24 h and 42 d postexposure, lungs were lavaged with saline. The first bronchoalveolar lavage (BAL) fluid supernatant was analyzed for lactate dehydrogenase (LDH) activity, levels of albumin, tumor necrosis factor-alpha (TNF-alpha), and macrophage inflammatory protein-2 (MIP-2), as well as total antioxidant capacity (TAC). The cellular fraction of the total BAL was used to determine alveolar macrophage (AM) and polymorphonuclear leukocyte (PMN) counts, and zymosanstimulated AM chemiluminescence (AM-CL). In separate mice, lung histopathological changes were evaluated 42 d postexposure. Acute (24-h) silica exposure decreased AMs, increased PMNs, increased LDH activity and levels of albumin, TNF-alpha, and MIP-2 in BAL fluid, and enhanced AM-CL in both iNOS KO and WT mice. However, iNOS KO mice exhibited less AM activation (defined as increased AM-CL and decreased AM yield) than WT. Furthermore, TAC following acute silica decreased in WT but was maintained in iNOS KO mice. Pulmonary reactions to subchronic (42 d) silica exposure were similar to acute. However, histopathological and BAL fluid indices of lung damage and inflammation, AM activation, and lung hydroxyproline levels were significantly less in iNOS KO compared to WT mice. These results suggest that iNOS-derived NO contributes to the pathogenesis of silica-induced lung disease in this mouse model.
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PMID:Role of inducible nitric oxide synthase-derived nitric oxide in silica-induced pulmonary inflammation and fibrosis. 1520 31

Diesel exhaust particles (DEPs) at three concentrations (5, 35, and 50 mg/kg body weight) were instilled into rats intratracheally. We studied gene expression at 1, 7, and 30 days postexposure in cells obtained by bronchoalveolar lavage (BAL) and in lung tissue. Using real-time reverse transcriptase-polymerase chain reaction (RT-PCR), we measured the mRNA levels of eight genes [interleukin (IL)-1beta, IL-6, IL-10, iNOS (inducible nitric oxide synthase), MCP-1 (monocyte chemoattractant protein-1), MIP-2 (macrophage inflammatory protein-2), TGF-beta1 (transforming growth factor-beta1), and TNF-alpha (tumor necrosis factor-alpha )] in BAL cells and four genes [IL-6, ICAM-1 (intercellular adhesion molecule-1), GM-CSF (granulocyte/macrophage-colony stimulating factor), and RANTES (regulated upon activation normal T cell expressed and secreted)] in lung tissue. In BAL cells on day 1, high-dose exposure induced a significant up-regulation of IL-1beta, iNOS, MCP-1, and MIP-2 but no change in IL-6, IL-10, TGF-beta1, and TNF-alpha mRNA levels. There was no change in the mRNA levels of IL-6, RANTES, ICAM-1, and GM-CSF in lung tissue. Nitric oxide production and levels of MCP-1 and MIP-2 were increased in the 24-hr culture media of alveolar macrophages (AMs) obtained on day 1. IL-6, MCP-1, and MIP-2 levels were also elevated in the BAL fluid. BAL fluid also showed increases in albumin and lactate dehydrogenase. The cellular content in BAL fluid increased at all doses and at all time periods, mainly due to an increase in polymorphonuclear leukocytes. In vitro studies in AMs and cultured lung fibroblasts showed that lung fibroblasts are a significant source of IL-6 and MCP-1 in the lung.
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PMID:Time course of gene expression of inflammatory mediators in rat lung after diesel exhaust particle exposure. 1586 72

The first epithelial surface encountered by inhaled materials is the epithelium of the respiratory tract. The epithelium is lined by a fluid (ELF) that can be sampled by a saline wash (lavage) of the area of interest. This technique, known as bronchoalveolar lavage (BAL), provides a means of sampling a body fluid that can provide valuable information on the reaction of the lung to inhaled materials. The most common responses measured are indicators of an inflammatory response, the most sensitive of which is an influx of neutrophils. In the extracellular fluid, levels of beta-glucuronidase activity indicate activation of macrophages, and lactate dehydrogenase activity indicates cytotoxicity. Other pro- and anti-inflammatory soluble factors that can be measured in BAL fluid include secretory products of macrophages and epithelial cells, such as tumor necrosis factor alpha, fibronectin, interleukin-1, various chemotactic factors (including IL-8, MIP-2), growth factors, proteases, and antiproteases. Oxidative stress can be measured by the levels of reduced glutathione in ELF, and increased levels of alkaline phosphatase indicate increased Type II cell secretions. Allergic responses are indicated by increased eosinophils and factors such as histamine and arachidonate metabolites in BAL fluid. BAL analysis can be used as a complementary technique with more traditional measures of lung injury, such as histopathology or radiology. The advantage of BAL analysis is that one can pick up early indicators of biochemical changes leading to later morphological changes in a disease process. A second advantage is that the BAL fluid analyses are quantitative, and dose-response measures can be obtained. In large animals, one can do repeated lavages to follow a disease process; in small animals, one can use serial sacrifices in similarly exposed rodents to achieve the same goal. Research related to the use of BAL fluid analyses to detect lung damage has been conducted at the Lovelace Respiratory Research Institute with funding from various sources including the US Department of Energy and the US Environmental Protection Agency.
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PMID:Use of bronchoalveolar lavage to detect respiratory tract toxicity of inhaled material. 1609 23

Previous studies have reported little correlation between the relative toxicity of particle types when comparing lung toxicity rankings following in vivo instillation versus in vitro cell culture exposures. This study was designed to assess the capacity of in vitro screening studies to predict in vivo pulmonary toxicity of several fine or nanoscale particle types in rats. In the in vivo component of the study, rats were exposed by intratracheal instillation to 1 or 5 mg/kg of the following particle types: (1) carbonyl iron (CI), (2) crystalline silica (CS) (Min-U-Sil 5, alpha-quartz), (3) precipitated amorphous silica (AS), (4) nano-sized zinc oxide (NZO), or (5) fine-sized zinc oxide (FZO). Depending on particle type and solution state, these particles range in size from 90 to 500 nm in size. Following exposures, the lungs of exposed rats were lavaged and inflammation (neutrophil recruitment) and cytotoxicity end points (bronchoalveolar lavage [BAL] fluid lactate dehydrogenase [LDH] values) were measured at 24 h, 1 week, 1 and 3 months postexposure. For the in vitro component of the study, three different culture conditions were utilized. Cultures of (1) rat L2 lung epithelial cells, (2) primary alveolar macrophages (AMs) (collected via BAL from unexposed rats), as well as (3) AM-L2 lung epithelial cell cocultures were incubated with the particle types listed above, and the culture fluids were evaluated for cytotoxicity end points (LDH, 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan [MTT]) as well as inflammatory cytokines (macrophage inflammatory 2 protein [MIP-2], tumor necrosis factor alpha [TNF-alpha], and interleukin-6 [IL-6]) at one (i.e., cytokines) or several (cytotoxicity) time periods. Results of in vivo pulmonary toxicity studies demonstrated that instilled CI particles produced little toxicity. CS particles produced sustained inflammation and cytotoxicity. AS particles produced reversible and transient inflammatory responses. NZO or FZO particles produced potent but reversible inflammation which was resolved by 1 month postinstillation exposure. Results of in vitro pulmonary cytotoxicity studies demonstrated a variety of responses to the different particle types, primarily at high doses. With respect to the LDH results, L2 cells were the most sensitive and exposures to nano- or fine-sized ZnO for 4 or 24 h were more cytotoxic than exposures to CS or AS particles. Macrophages essentially were resistant and epithelial macrophage cocultures generally reflected the epithelial results at 4 and 24 h incubation, but not at 48 h incubation. MTT results were also interesting but, except for nano- and fine-sized ZnO, did not correlate well with LDH results. Results of in vitro pulmonary inflammation studies demonstrated that L2 cells did not produce MIP-2 cytokines, but CS- or AS-exposed AMs and, to a lesser degree, cocultures secreted these chemotactic factors into the culture media. Measurements of TNF-alpha in the culture media by particle-exposed cells demonstrated little activity. In addition, IL-6 secretion was measured in CS, AS, and nano-sized ZnO-exposed cocultures. When considering the range of toxicity end points to five different particle types, the comparisons of in vivo and in vitro measurements demonstrated little correlation, particularly when considering many of the variables assessed in this study-such as cell types to be utilized, culture conditions and time course of exposure, as well as measured end points. It seems clear that in vitro cellular systems will need to be further developed, standardized, and validated (relative to in vivo effects) in order to provide useful screening data on the relative toxicity of inhaled particle types.
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PMID:Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity profiles. 1730 Oct 66

In order to explore the potential mechanism that animals with cardiopulmonary diseases were more susceptible than healthy animals, the spontaneously hypertensive rats (SHR) as a model of human cardiovascular disease were used. SHR and wistar kyoto rats (WKY) were exposed by intratracheal instillation to fine particles with the doses of 0.0 (saline), 1.6, 8.0 and 40.0mg/kg body weight, respectively. The exposure was done once a day, for three continuous days. The rats were killed after 24h following the last exposure, followed by analysis of bronchoalveolar lavage fluid (BALF) to estimate the lung injury. Meantime, parameters of oxidative stress, cytokines and cell surface receptors related to inflammation and anti-inflammation were also measured. The results showed that lactate dehydrogenase (LDH) activity, percentages of neutrophils and lymphocytes, and expression of TBA-reactive substances and cytokines (IL-1beta, TNF-alpha, MIP-2, OPN, NF-kappaB, CC16 and HO-1) and cell surface receptors (CD44 and TLR-4) were increased in rats, but percentage of macrophages decreased. Meanwhile, at the same dose exposed, the levels of those parameters were higher in SHR than that in WKY rats. The results indicated that inflammation might be one of the mechanisms of lung injury induced by fine particles. Results of comparisons of different response to fine particles between SHR and WKY rats suggested that lung injury induced by fine particles was greater in SHR than that in WKY rats.
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PMID:Pulmonary responses to fine particles: differences between the spontaneously hypertensive rats and wistar kyoto rats. 1760 36

In this study, we have investigated the role of the cannabinoid CB(2) (CB(2)) receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB(2) receptor in TNF-alpha-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB(2) receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-alpha, MIP-1alpha, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF-alpha-induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB(2) receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB(2) receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.
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PMID:Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis. 1765 47


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