Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Partial-thickness skin burns have been shown to induce neutrophil-dependent microvascular injury both locally (skin) and systemically (lung). In the present study, interventional measures to block inflammatory chemoattractants were employed to define the pathophysiologic role of these mediators in the development of secondary lung injury following thermal injury of skin. Rats were treated with blocking antibodies to either C5a or to the alpha-chemokines, keratinocyte-derived cytokine (KC), or macrophage inflammatory protein-2 (MIP-2). To study the role of platelet activating factor, a receptor antagonist (PAF-Ra) was utilized. The development of lung vascular injury following thermal injury to skin was significantly attenuated by treatment with anti-C5a (84%), anti-KC (67%), and anti-MIP-2 (77%), but treatment with PAF-Ra had no protective effects. Protective interventions were paralleled by significant reductions in the tissue buildup of myeloperoxidase. When bronchoalveolar lavage fluids from thermally injured rats were evaluated, elevations in TNF;ZA and IL-1 were found and were determined to be C5a-dependent (but unaffected by treatment with PAF-Ra). These studies indicate that lung tissue injury after thermal skin burns is dependent on chemotactic mediators. The data also suggest that lung expression of TNFalpha and IL-1 after thermal injury of skin is C5a-dependent.
Exp Mol Pathol 1999 Aug
PMID:Chemotactic mediator requirements in lung injury following skin burns in rats. 1048 40

The sodium-hydrogen exchanger isoform, NHE-3 is essential for the absorption of sodium and water from intestine. Whether this protein plays any role in inflammatory bowel disease is less understood. To address this issue, NHE-3 mRNA and protein levels were estimated in the terminal ileum and colon of the rats having colitis induced with trinitrobenzenesulphonic acid (TNBS). The effect of garlic (Allium sativum) was also evaluated on the expression of NHE-3. The animals were treated with garlic extract intraperitoneally starting 2 h before the TNBS administration until day 4 post-TNBS administration and were sacrificed on day 5. In control animals, the levels of NHE-3 in colon was higher than the ileum. As a result of colitis, the levels of NHE-3 protein and mRNA increased both in the colon and terminal ileum. Garlic treatment of the colitic animals resulted in a selective suppression of NHE-3 in the terminal ileum. Colitis caused an induction of the myeloperoxidase activity, the marker of inflammation in the colon but not in the ileum. These findings suggest that induction of NHE-3 is not primarily due to inflammation. Selective suppression of this protein in ileum by garlic may cause loss of sodium chloride and water during colitis.
Mol Cell Biochem 1999 Oct
PMID:Altered expression of the Na+/H+ exchanger isoform-3 in experimental colitis: effect of garlic. 1056 86

The flavonoid antioxidant silymarin is used clinically in Europe and Asia for the treatment of liver diseases and is sold in the United States and Europe as a dietary supplement. Recently we showed that silymarin possesses exceptionally high cancer-preventive effects in different mouse skin carcinogenesis models and affords strong anticancer effects in human skin, cervical, prostate, and breast carcinoma cells. More recently, we showed that the anti-tumor-promoting effect of silymarin is primarily targeted against stage I tumor promotion in mouse skin (Cancer Res 1999;59:622-632). Based on this recent study, in this report, further investigations were made to identify and define the biochemical and molecular mechanisms of silymarin's effect during stage I tumor promotion in mouse skin. A single topical application of silymarin at 3-, 6-, and 9-mg doses onto SENCAR mouse skin followed 30 min later with 12-O-tetradecanoylphorbol 13-acetate (TPA) at a 3-microg dose resulted in a 76-95% inhibition (P < 0.001) of TPA-caused skin edema. Similarly, these doses of silymarin also showed 39-90%, 29-85%, and 15-67% protection (P < 0.05 or 0.001), against TPA-caused depletion of epidermal superoxide dismutase, catalase, and glutathione peroxidase activity, respectively. Pretreatment of mice with silymarin also produced highly significant inhibition of TPA-caused induction of epidermal lipid peroxidation (47-66% inhibition, P < 0.001) and myeloperoxidase activity (56-100% inhibition, P < 0.001). In additional studies assessing the effect of silymarin on arachidonic acid metabolism pathways involving lipoxygenase and cyclooxygenase (COX), similar doses of silymarin showed highly significant inhibition of TPA-caused induction of epidermal lipoxygenase (49-77% inhibition, P < 0.001) and COX (35-64% inhibition, P < 0.01 or 0.001) activity. Western immunoblot analysis showed that the observed effect of silymarin on COX activity was due to inhibition of TPA-inducible COX-2 with no change in constitutive COX-1 protein levels. In other studies, silymarin also showed dose-dependent inhibition of TPA-caused induction of epidermal interleukin 1alpha (IL-1alpha) protein (39-72% inhibition, P < 0.005 or 0.001) and mRNA expression. Taken together, the results from these biochemical and molecular studies further substantiate our recent observation of silymarin's anti-tumor-promoting effects primarily at stage I tumor promotion. Furthermore, the observed inhibitory effects of silymarin on COX-2 and IL-1alpha should be further explored to develop preventive strategies against those cancers in which these molecular targets play one of the causative roles, such as non-melanoma skin, colon, and breast cancers in humans.
Mol Carcinog 1999 Dec
PMID:Significant inhibition by the flavonoid antioxidant silymarin against 12-O-tetradecanoylphorbol 13-acetate-caused modulation of antioxidant and inflammatory enzymes, and cyclooxygenase 2 and interleukin-1alpha expression in SENCAR mouse epidermis: implications in the prevention of stage I tumor promotion. 1056 9

In a two-hit model of acid aspiration lung injury, mice were subjected to nonlethal cecal ligation and puncture (CLP). After 48 h, intratracheal (IT) acid was administered, and mice were killed at several time points. Recruitment of neutrophils in response to acid was documented by myeloperoxidase assay and neutrophil counts in bronchoalveolar lavage (BAL) fluid and peaked at 8 h post-IT injection. Albumin in BAL fluid, an indicator of lung injury, also peaked at 8 h. When the contributions of the two hits were compared, neutrophil recruitment and lung injury occurred in response to acid but were not greatly influenced by addition of another hit. Neutrophil sequestration was preceded by elevations in KC and macrophage inflammatory protein-2alpha in plasma and BAL fluid. KC levels in BAL fluid were higher and peaked earlier than macrophage inflammatory protein-2alpha levels. When KC was blocked with specific antiserum, neutrophil recruitment was significantly reduced, whereas albumin in BAL fluid was not affected. In conclusion, murine KC mediated neutrophil recruitment but not lung injury in a two-hit model of aspiration lung injury.
Am J Physiol Lung Cell Mol Physiol 2000 Mar
PMID:Immunopathology of a two-hit murine model of acid aspiration lung injury. 1071 May 23

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in the pathogenesis of either human and experimental myocardial ischaemia. Tacrolimus, formerly known as FK506, has been previously shown to display cardioprotective effects on experimental ischaemia/reperfusion-induced myocardial damage. This study investigated whether cardioprotection induced by tacrolimus in myocardial ischaemia-reperfusion (MI/R) injury might be due to inhibition of the nuclear factor kappa B (NF- kappaB) that in turn causes reduced cardiac ICAM-1 expression and blunted polymorphonuclear leukocyte accumulation. Anaesthetized rats were subjected to total occlusion (45 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham myocardial ischaemia-reperfusion rats (Sham MI/R) were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity, serum creatine kinase (CK) activity, cardiac mRNA for ICAM-1 reverse-transcriptase polymerase chain reaction, the inhibitory protein of NF- kappaB I kappaB alpha (Western blot analysis) in the myocardium-at-risk, and left ventricle d P/d t(max)were evaluated. Myocardial ischaemia plus reperfusion in untreated rats produced marked myocardial necrosis, increased serum CK activity and myeloperoxidase activity (MPO, a marker of leukocyte accumulation) both in the area at risk and in the necrotic area, and reduced the left ventricle dP/d t(max). Furthermore, inhibitory protein I kappaB alpha levels decreased, and cardiac mRNA for ICAM-1 increased, after 0.5 and 5 h of reperfusion, respectively. Administration of tacrolimus (25, 50 and 100microg/kg as an i.v. infusion 5 min after reperfusion) lowered myocardial necrosis and myeloperoxidase activity in the area at risk and in necrotic area, decreased serum CK activity, increased left ventricle dP/d t(max), reduced the loss the of inhibitory protein I kappaB alpha and blunted the message for ICAM-1. The present data suggest that tacrolimus blocks the early activation of the transcription factor NF- kappaB, suppresses ICAM-1 gene activation, reduces leukocyte accumulation and protects against myocardial ischaemia-reperfusion injury.
J Mol Cell Cardiol 2000 Mar
PMID:Tacrolimus limits polymorphonuclear leucocyte accumulation and protects against myocardial ischaemia- reperfusion injury. 1073 42

The genes encoding Hoxa9 and Meis1 are transcriptionally coactivated in a subset of acute myeloid leukemia (AML) in mice. In marrow reconstitution experiments, coexpression of both genes produces rapid AML, while neither gene alone generates overt leukemia. Although Hoxa9 and Meis1 can bind DNA as heterodimers, both can also heterodimerize with Pbx proteins. Thus, while their coactivation may result from the necessity to bind promoters as heterodimers, it may also result from the necessity of altering independent biochemical pathways that cooperate to generate AML, either as monomers or as heterodimers with Pbx proteins. Here we demonstrate that constitutive expression of Hoxa9 in primary murine marrow immortalizes a late myelomonocytic progenitor, preventing it from executing terminal differentiation to granulocytes or monocytes in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3. This immortalized phenotype is achieved in the absence of endogenous or exogenous Meis gene expression. The Hoxa9-immortalized progenitor exhibited a promyelocytic transcriptional profile, expressing PU.1, AML1, c-Myb, C/EBP alpha, and C/EBP epsilon as well as their target genes, the receptors for GM-CSF, G-CSF, and M-CSF and the primary granule proteins myeloperoxidase and neutrophil elastase. G-CSF obviated the differentiation block of Hoxa9, inducing neutrophilic differentiation with accompanying expression of neutrophil gelatinase B and upregulation of gp91phox. M-CSF also obviated the differentiation block, inducing monocytic differentiation with accompanying expression of the macrophage acetyl-low-density lipoprotein scavenger receptor and F4/80 antigen. Versions of Hoxa9 lacking the ANWL Pbx interaction motif (PIM) also immortalized a promyelocytic progenitor with intrinsic biphenotypic differentiation potential. Therefore, Hoxa9 evokes a cytokine-selective block in differentiation by a mechanism that does not require Meis gene expression or interaction with Pbx through the PIM.
Mol Cell Biol 2000 May
PMID:Hoxa9 immortalizes a granulocyte-macrophage colony-stimulating factor-dependent promyelocyte capable of biphenotypic differentiation to neutrophils or macrophages, independent of enforced meis expression. 1075 11

The determination by protein chemistry methods of the half-cystine status in human eosinophil peroxidase (EPO) is reported. EPO is two-chained and has a total of 14 half-cystine residues. Cys141 and Cys152 form an intrachain bridge in the light chain of EPO. Disulfide bridges connect Cys253 and Cys263, Cys257 and Cys287, Cys359 and Cys370, Cys570 and Cys635, and Cys676 and Cys701, forming five intrachain disulfide bridges in the heavy chain of EPO. Cys291 and Cys455 are found to be unpaired, containing free sulfhydryl groups. The pattern of disulfide bridges is in agreement with that predicted from the X-ray crystallographic structure of canine myeloperoxidase (MPO) (Zeng, J., and Fenna, R. E. (1992) J. Mol. Biol. 226, 185-207) to be general for the class of mammalian peroxidases, including EPO, MPO, lactoperoxidase (LPO), and thyroid peroxidase (TPO). Of four candidate sites in EPO for attachment of glucosamine-based carbohydrate, Asn327 and Asn363 are occupied, whereas Asn700 and Asn708 are unsubstituted. Furthermore, a discrepancy in the literature regarding the sequence of residues 645-659 is resolved.
 ...
PMID:The status of half-cystine residues and locations of N-glycosylated asparagine residues in human eosinophil peroxidase. 1086 52

Cystic fibrosis (CF) is a condition characterized by neutrophil-mediated lung damage and bacterial colonization. The physiological basis for reported functional alterations in CF neutrophils, including increased release of neutrophil elastase, myeloperoxidase, and oxidants, is unknown. These processes are, however, regulated by intracellular pH (pH(i)). We demonstrate here that pH(i) regulation is altered in neutrophils from CF patients. Although resting pH(i) is similar, pH(i) after acid loading and activation (N-formyl-methionyl-leucyl-phenylalanine and phorbol 12-myristate 13-acetate) is more acidic in CF cells than in normal cells. Furthermore, patients with non-CF-related bronchiectasis handle acid loading and activation in a fashion similar to subjects with normal neutrophils, suggesting that chronic pulmonary inflammation alone does not explain the difference in pH(i). This is further supported by data showing that normal neutrophils exposed to the CF pulmonary milieu respond by increasing pH(i) as opposed to decreasing pH(i) as seen in activated CF neutrophils. These pH(i) differences in activated or acid-loaded CF neutrophils are abrogated by ZnCl(2) but not by amiloride and bafilomycin A(1), suggesting that passive proton conductance is abnormal in CF. In addition, DIDS, which inhibits HCO(3)(-)/Cl(-) exchange, causes alkalinization of control but not of CF neutrophils, suggesting that anion transport is also abnormal in CF neutrophils. In summary, we have shown that pH(i) regulation in CF neutrophils is intrinsically abnormal, potentially contributing to the pulmonary manifestations of the condition.
Am J Physiol Lung Cell Mol Physiol 2000 Jul
PMID:Altered intracellular pH regulation in neutrophils from patients with cystic fibrosis. 1089 4

Lung lavage fluid of patients with acute lung injury (ALI) has increased levels of interleukin-1 (IL-1) and neutrophils, but their relationship to the lung leak that characterizes these patients is unclear. To address this concern, we investigated the role of the neutrophil agonist platelet-activating factor [1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF)] in the development of the acute neutrophil-dependent lung leak that is induced by giving IL-1 intratracheally to rats. We found that PAF acetyltransferase and PAF activities increased in lungs of rats given IL-1 intratracheally compared with lungs of sham-treated rats given saline intratracheally. The participation of PAF in the development of lung leak and lung neutrophil accumulation after IL-1 administration was suggested when treatment with WEB-2086, a commonly used PAF-receptor antagonist, decreased lung leak, lung myeloperoxidase activity, and lung lavage fluid neutrophil increases in rats given IL-1 intratracheally. Additionally, neutrophils recovered from the lung lavage fluid of rats given IL-1 intratracheally reduced more nitro blue tetrazolium (NBT) in vitro than neutrophils recovered from control rats or rats that had been given WEB-2086 and then IL-1. Histological examination indicated that the endothelial cell-neutrophil interfaces of cerium chloride-stained lung sections of rats given IL-1 contained increased cerium perhydroxide (the reaction product of cerium chloride with hydrogen peroxide) compared with lungs of control rats or rats treated with WEB-2086 and then given IL-1 intratracheally. These in vivo findings were supported by parallel findings showing that WEB-2086 treatment decreased neutrophil adhesion to IL-1-treated cultured endothelial cells in vitro. We concluded that PAF contributes to neutrophil recruitment and neutrophil activation in lungs of rats given IL-1 intratracheally.
Am J Physiol Lung Cell Mol Physiol 2000 Jul
PMID:Platelet-activating factor contributes to acute lung leak in rats given interleukin-1 intratracheally. 1089 5

Cystic fibrosis (CF) is associated with chronic pulmonary inflammation and progressive lung dysfunction, possibly associated with the formation of neutrophil myeloperoxidase (MPO)-derived oxidants. Expectorated sputum specimens from adult CF patients were analyzed for MPO characteristic protein modifications and found to contain large amounts of active MPO as well as high levels of protein-associated 3-chlorotyrosine and 3,3'-dityrosine, products that result from MPO activity, compared with expectorated sputum from non-CF subjects. Sputum levels of nitrite (NO(2)(-)) and nitrate (NO(3)(-)), indicating local production of nitric oxide (NO. ), were not elevated but in fact were slightly reduced in CF. However, there was a slight increase in protein-associated 3-nitrotyrosine in CF sputum compared with controls, reflecting the formation of reactive nitrogen intermediates, possibly through MPO-catalyzed oxidation of NO(2)(-). CF sputum MPO was found to contribute to oxidant-mediated cytotoxicity toward cultured tracheobronchial epithelial cells; however, peroxidase-dependent protein oxidation occurred primarily within sputum proteins, suggesting scavenging of MPO-derived oxidants by CF mucus and perhaps formation of secondary cytotoxic products within CF sputum. Our findings demonstrate the formation of MPO-derived oxidizing and possibly nitrating species within the respiratory tract of subjects with CF, which collectively may contribute to bronchial injury and respiratory failure in CF.
Am J Physiol Lung Cell Mol Physiol 2000 Sep
PMID:Myeloperoxidase and protein oxidation in cystic fibrosis. 1095 29


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