Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydroquinone is a toxic compound and a major benzene metabolite. We report that it strongly inhibits the activation of macrophages and associated cells. Thus, it suppressed the production of proinflammatory cytokines [tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-3, IL-6, IL-10, IL-12p40, IL-23], secretion of toxic molecules [nitric oxide (NO) and reactive oxygen species (ROS)] and the activation and expression of CD29 as judged by cell-cell adhesion and surface staining experiments. The inhibition was due to the induction of heme oxygenase (HO)-1 in LPS-activated macrophages, since blocking HO-1 activity with ZnPP, an HO-1 specific inhibitor, abolished hydroquinone's NO inhibitory activity. In addition, hydroquinone and inhibitors (wortmannin and LY294002) of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway had very similar inhibitory effects on LPS-induced and CD29-mediated macrophage responses, including the phosphorylation of Akt. Therefore, our data suggest that hydroquinone inhibits macrophage-mediated immune responses by modulating intracellular signaling and protective mechanisms.
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PMID:Hydroquinone, a reactive metabolite of benzene, reduces macrophage-mediated immune responses. 1746 97

Pulmonary arterial hypertension (PAH) is a fatal disease associated with inflammation and pathological remodeling of the pulmonary artery (PA). Interleukin (IL)-10 is a pleiotropic antiinflammatory cytokine with vasculoprotective properties. Here, we report the preventive effects of IL-10 on monocrotaline-induced PAH. Three-week-old Wistar rats were intramuscularly injected with an adeno-associated virus serotype 1 vector expressing IL-10, followed by monocrotaline injection at 7 weeks old. IL-10 transduction significantly improved survival rates of the PAH rats 8 weeks after monocrotaline administration compared with control gene transduction (75% versus 0%, P<0.01). IL-10 also significantly reduced mean PA pressure (22.8+/-1.5 versus 29.7+/-2.8 mm Hg, P<0.05), a weight ratio of right ventricle to left ventricle plus septum (0.35+/-0.04 versus 0.42+/-0.05, P<0.05), and percent medial thickness of the PA (12.9+/-0.3% versus 21.4+/-0.4%, P<0.01) compared with controls. IL-10 significantly reduced macrophage infiltration and vascular cell proliferation in the remodeled PA in vivo. It also significantly decreased the lung levels of transforming growth factor-beta1 and IL-6, which are indicative of PA remodeling. In addition, IL-10 increased the lung level of heme oxygenase-1, which strongly prevents PA remodeling. In vitro analysis revealed that IL-10 significantly inhibited excessive proliferation of cultured human PA smooth muscle cells treated with transforming growth factor-beta1 or the heme oxygenase inhibitor tin protoporphyrin IX. Thus, IL-10 prevented the development of monocrotaline-induced PAH, and these results provide new insights into the molecular mechanisms of human PAH.
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PMID:Interleukin-10 expression mediated by an adeno-associated virus vector prevents monocrotaline-induced pulmonary arterial hypertension in rats. 1767 72

Pro-inflammatory cytokines, matrix metalloproteinases (MMPs) and other catabolic factors participate in the pathogenesis of cartilage damage in osteoarthritis (OA). Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) mediate cartilage degradation and might be involved in the progression of OA. Previously, we found that haem oxygenase-1 (HO-1) is down-regulated by pro-inflammatory cytokines and up-regulated by IL-10 in OA chondrocytes. The aim of this study was to determine whether HO-1 can modify the catabolic effects of IL-1beta in OA cartilage and chondrocytes. Up-regulation of HO-1 by cobalt protoporphyrin IX significantly reduced glycosaminoglycan degradation elicited by IL-1beta in OA cartilage explants but increased glycosaminoglycan synthesis and the expression of collagen II in OA chondrocytes in primary culture, as determined by radiometric procedures, immunoblotting and immunocytochemistry. HO-1 decreased the activation of extracellular signal-regulated kinase 1/2. This was accompanied by a significant inhibition in MMP activity and expression of collagenases MMP-1 and MMP-13 at the protein and mRNA levels. In addition, HO-1 induction caused a significant increase in the production of insulin-like growth factor-1 and a reduction in the levels of insulin-like growth factor binding protein-3. We have shown in primary culture of chondrocytes and articular explants from OA patients that HO-1 counteracts the catabolic and anti-anabolic effects of IL-1beta. Our data thus suggest that HO-1 may be a factor regulating the degradation and synthesis of extracellular matrix components in OA.
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PMID:Haem oxygenase-1 regulates catabolic and anabolic processes in osteoarthritic chondrocytes. 1820 Jun 30

Microvascular failure is a major determinant for the development of hepatocellular dysfunction after hemorrhagic shock. Induction of heme oxygenase (HO) 1 may confer hepatocellular protection. Hemin arginate (HAR) induces HO-1 and protects against shock-induced organ failure. The mechanisms are not completely understood, but HO-1-mediated protective effects on the microcirculation and on the inflammatory response may contribute. Therefore, the aim of the present study was to investigate the influence of HAR pretreatment on liver microcirculation and cytokine response to assess the role of HO-1-mediated effects under these conditions. Male Sprague-Dawley rats (200-300 g; n=8 per group) were subjected to hemorrhage (MAP, 30-40 mmHg for 1 h) 24 h after pretreatment with vehicle (Ringer solution) or HAR (5 mg kg(-1)), followed by 2 h of resuscitation. The microcirculation and the redox state (nicotinamide adenine dinucleotide phosphate [reduced form; NADPH] autofluorescence) of the liver were assessed using intravital microscopy. Cytokine levels (TNF-alpha and IL-10) were quantified using an enzyme-linked immunosorbent assay. A profound induction of HO-1 was observed 24 h after pretreatment with HAR. Hemorrhage significantly reduced sinusoidal perfusion and increased NADPH autofluorescence and cytokine levels. Hemin arginate pretreatment significantly improved liver microcirculation, reduced NADPH autofluorescence, significantly increased IL-10, and tended to decrease TNF-alpha serum levels compared with shock vehicle. Blockade of the HO pathway with tin-mesoporphyrin-IX after HAR pretreatment abolished the observed beneficial effects, whereas the additional administration of the carbon monoxide donor dichloromethane reversed the tin-mesoporphyrin-IX-mediated changes. These results suggest that HAR pretreatment improves liver microcirculation and mediates an anti-inflammatory cytokine response after hemorrhagic shock through induction of HO-1 and in part through an increased carbon monoxide release.
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PMID:Hemin arginate-induced heme oxygenase 1 expression improves liver microcirculation and mediates an anti-inflammatory cytokine response after hemorrhagic shock. 1841 32

Ischemia and reperfusion injury (IRI) contributes to the development of chronic interstitial fibrosis/tubular atrophy in renal allograft patients. Cyclooxygenase (COX) 1 and 2 actively participate in acute ischemic injury by activating endothelial cells and inducing oxidative stress. Furthermore, blockade of COX 1 and 2 has been associated with organ improvement after ischemic damage. The aim of this study was to evaluate the role of COX 1 and 2 in the development of fibrosis by performing a COX 1 and 2 blockade immediately before IRI. We subjected C57Bl/6 male mice to 60 min of unilateral renal pedicle occlusion. Prior to surgery mice were either treated with indomethacin (IMT) at days -1 and 0 or were untreated. Blood and kidney samples were collected 6 wks after IRI. Kidney samples were analyzed by real-time reverse transcription-polymerase chain reaction for expression of transforming growth factor beta (TGF-beta), monocyte chemoattractant protein 1 (MCP-1), osteopontin (OPN), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1 beta, IL-10, heme oxygenase 1 (HO-1), vimentin, connective-tissue growth factor (CTGF), collagen I, and bone morphogenic protein 7 (BMP-7). To assess tissue fibrosis we performed morphometric analyses and Sirius red staining. We also performed immunohistochemical analysis of anti-actin smooth muscle. Renal function did not significantly differ between groups. Animals pretreated with IMT showed significantly less interstitial fibrosis than nontreated animals. Gene transcript analyses showed decreased expression of TGF-beta, MCP-1, TNF-alpha, IL-1-beta, vimentin, collagen I, CTGF, and IL-10 mRNA (all P < 0.05). Moreover, HO-1 mRNA was increased in animals pretreated with IMT (P < 0.05). Conversely, IMT treatment decreased osteopontin expression and enhanced BMP-7 expression, although these levels did not reach statistical significance when compared with control expression levels. The blockade of COX 1 and 2 resulted in less tissue fibrosis, which was associated with a decrease in proinflammatory cytokines and enhancement of the protective cellular response.
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PMID:Inhibition of COX 1 and 2 prior to renal ischemia/reperfusion injury decreases the development of fibrosis. 1876 37

Understanding "two-hit" experimental models is crucial for the rational development of therapies for hemorrhagic shock (HS). We modeled the clinical scenario of HS followed by polymicrobial sepsis (cecal ligation and puncture [CLP]) to investigate the molecular and functional alterations that occur within the gastrointestinal tract. Control, HS, CLP, simultaneous HS + CLP, and HS + delayed CLP by 24 h groups of Sprague-Dawley rats were studied for gastrointestinal transit and in vitro colonic circular muscle contractility to bethanechol. Reverse transcription-polymerase chain reaction quantified IL-6, IL-10, and heme oxygenase 1 messenger RNA expression in the isolated colonic muscularis 6 h after insult. Myeloperoxidase-positive neutrophils were quantified in colonic muscularis whole mounts. Mortality at 24 h was significantly increased in simultaneous mild HS + CLP (88%) over control, mild HS, CLP alone, or HS + delayed CLP. Cecal ligation and puncture significantly delayed transit compared with controls and HS alone. Hemorrhagic shock + delayed CLP animals had normal transit. Colonic contractions were suppressed by 50% after CLP compared with controls and HS. In contrast, HS + delayed CLP displayed control levels of contractile responses to bethanechol. Cecal ligation and puncture and simultaneous HS + CLP caused significant inflammatory messenger RNA induction of IL-6, iNOS, IL-10, and heme oxygenase 1 compared with control and HS, and these responses were significantly suppressed in HS + delayed CLP colonic muscularis extracts. Neutrophils were significantly recruited into the colonic muscularis following CLP after 24 h compared with control and HS. This recruitment was significantly less in the HS + delayed CLP animals. These data demonstrate the ability of mild HS to precondition the animal and protect it against a delayed, but not simultaneous, polymicrobial event.
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PMID:Interaction of hemorrhagic shock and subsequent polymicrobial sepsis on gastrointestinal motility. 1879 97

Acute lung injury (ALI) leading to respiratory distress is a common sequela of shock or trauma. The toll-like receptors (TLRs) stand at the interface of innate immune activation in the settings of both infection and sterile injury by responding to a variety of microbial and endogenous ligands alike. This work explored the effects of TLR-4 on hemorrhage-induced ALI and characterizes the signaling pathways and the mechanisms involved in noninfectious ALI. Mice underwent hemorrhagic shock and resuscitation (HSR). Arterial blood gases; expressions of TLR-4, heme oxygenase 1 (HO-1), and p38 mitogen-activated protein kinase (p38MAPK); myeloperoxidase activity; lung wet/dry ratios; and IL-10 levels in lung tissues were obtained at 6, 24, and 48 h after HSR. Hemorrhagic shock and resuscitation induced significant expressions of TLR-4, HO-1, and p38MAPK in C3H/HeN mice. IL-10 and myeloperoxidase were markedly increased at 24 h after HSR, and C3H/HeN mice had ALI with PaO2/fraction of inspired oxygen less than 300 mmHg. The induced amount of each cytokine level and the expressions of TLR-4, HO-1, and p38MAPK of C3H/HeN mice were significantly higher compared with C3H/HeJ mice. This study demonstrated that lung p38MAPK is activated after HSR, and p38MAPK inhibitor FR167653 suppresses HO-1 induction after ALI. We concluded that TLR-4 might induce HO-1 messenger RNA expression, which is probably involved in p38MAPK activation in the development of the lung dysfunction after HSR.
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PMID:Toll-like receptor 4 regulates heme oxygenase-1 expression after hemorrhagic shock induced acute lung injury in mice: requirement of p38 mitogen-activated protein kinase activation. 1882 44

Previous studies have found that signaling by the estrogen receptor-beta (Er-beta) attenuated solar-simulated UV radiation (SSUV)-induced immunosuppression. This study seeks evidence for a common mechanism for this immunoprotection for both Er-beta signaling and irradiation with the UVA waveband. In Skh:hr-1 hairless mice, the immunoprotection afforded by UVA exposure against subsequent UVB or cis-urocanic acid suppression of contact hypersensitivity (CHS) was abrogated by treatment with the antiestrogen, ICI 182,780. Furthermore, in normal C57BL mice, UVA enrichment of UVA/UVB sources provided protection against UVB-suppressed CHS and upregulated epidermal IL-10 expression, but this protection was inhibited in Er-beta-/- mice. These observations indicated that the immunoprotective response to UVA was dependent on Er-beta signaling. As earlier studies have established that UVA photoimmune protection depends on the induction of the stress enzyme, heme oxygenase (HO)-1, its activity was examined relative to Er-beta. Immunoprotection against SSUV by 17-beta-estradiol was prevented by inhibiting HO enzyme activity; immunoprotection against cis-urocanic acid by carbon monoxide (HO product) was prevented by ICI 182,780. In addition, the HO-1 gene was unresponsive to UVA induction in Er-beta-/- mice. Therefore, HO-1 inducibility and Er-beta signaling are interdependent requisite responses to the UVA waveband for its immunoprotective action against UVB exposure.
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PMID:Interdependence between heme oxygenase-1 induction and estrogen-receptor-beta signaling mediates photoimmune protection by UVA radiation in mice. 1947 3

Induction of heme oxygenase (HO)-1 is a key defense mechanism against oxidative stress. Compared with tubules, glomeruli are refractory to HO-1 upregulation in response to injury. This can be a disadvantage as it may be associated with insufficient production of cytoprotective heme-degradation metabolites. We, therefore, explored whether 1) targeted HO-1 expression can be achieved in glomeruli without altering their physiological integrity and 2) this expression reduces proteinuria in immune injury induced by an anti-glomerular basement membrane (GBM) antibody (Ab). We employed a 4.125-kb fragment of a mouse nephrin promoter downstream to which a FLAG-tagged hHO-1 cDNA sequence was inserted and subsequently generated transgenic mice from the FVB/N parental strain. There was a 16-fold higher transgene expression in the kidney than nonspecific background (liver) while the transprotein immunolocalized in glomerular epithelial cells (GEC). There was no change in urinary protein excretion, indicating that GEC-targeted HO-1 expression had no effect on glomerular protein permeability. Urinary protein excretion in transgenic mice with anti-GBM Ab injury (days 3 and 6) was significantly lower compared with wild-type controls. There was no significant change in renal expression levels of profibrotic (TGF-beta1) or anti-inflammatory (IL-10) cytokines in transgenic mice with anti-GBM Ab injury. These observations indicate that GEC-targeted HO-1 expression does not alter glomerular physiological integrity and reduces proteinuria in glomerular immune injury.
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PMID:GEC-targeted HO-1 expression reduces proteinuria in glomerular immune injury. 1958 44

One of the early phases that lead to fibrosis progression is inflammation. Once this stage is resolved, fibrosis might be prevented. Bone marrow mononuclear cells (BMMCs) are emerging as a new therapy for several pathologies, including autoimmune diseases, because they enact immunosuppression. In this study we aimed to evaluate the role of BMMC administration in a model of kidney fibrosis induced by an acute injury. C57Bl6 mice were subjected to unilateral severe ischemia by clamping the left renal pedicle for 1h. BMMCs were isolated from femurs and tibia, and after 6h of reperfusion, 1 x 10(6) cells were administrated intraperitoneally. At 24h after surgery, treated animals showed a significant decrease in creatinine and urea levels when compared with untreated animals. Different administration routes were tested. Moreover, interferon (IFN) receptor knockout BMMCs were used, as this receptor is necessary for BMMC activation. Labeled BMMCs were found in ischemic kidney on FACS analysis. This improved outcome was associated with modulation of inflammation in the kidney and systemic modulation, as determined by cytokine expression profiling. Despite non-amelioration of functional parameters, kidney mRNA expression of interleukin (IL)-6 at 6 weeks was lower in BMMC-treated animals, as were levels of collagen 1, connective tissue growth factor (CTGF), transforming growth factor-beta (TGF-beta) and vimentin. Protective molecules, such as IL-10, heme oxygenase 1 (HO-1) and bone morphogenetic 7 (BMP-7), were increased in treated animals after 6 weeks. Moreover, Masson and Picrosirius red staining analyses showed less fibrotic areas in the kidneys of treated animals. Thus, early modulation of inflammation by BMMCs after an ischemic injury leads to reduced fibrosis through modulation of early inflammation.
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PMID:Bone marrow mononuclear cells attenuate fibrosis development after severe acute kidney injury. 2030 84


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