Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been proposed that oxidant stress of cells in the lung is one of the underlying mechanisms of particulate pollution-induced exacerbation of lung disease. Individuals who are considered most sensitive to particulate pollution are those with pre-existing airways inflammation, such as chronic obstructive pulmonary disease (COPD), lung infection or asthma. These diseases are characterized by a presence of inflammatory cells in the airways including neutrophils (PMN), eosinophils and monocytes (Mo), and increased numbers of alveolar macrophages (AM). These cells have a high capacity for production of oxygen radicals, as compared to other cell types of the lung. To assess the oxidative response of these various cell types to pollution particles of various sources, luminol-dependent chemiluminescence was employed. Particles including transition metal-rich residual oil fly ashes (ROFAs), coal fly ashes, diesel, SiO2, TiO2 and fugitive dusts were co-cultured with AM, Mo and PMN in a dose range of 10-100 microg/2 x 10(5) cells and chemiluminescence determined following a 20-min interaction. A strong oxidant response of AM was restricted to oil fly ashes, while the PMN were most reactive to the dusts containing aluminium silicate. In general, the Mo response was less vigorous, but overlapped both AM- and PMN-stimulating dusts. However, in response to SiO2 and volcanic ash the Mo chemiluminescence exceeded that of the other cell types. Oxygen radicals generated in response to ROFA by the AM were likely to be dependent on mitochondrial processes, while the response in PMN involved the membrane NADPH oxidase complex, as determined by targeting inhibitors. The response of AM to SiO2 of various sizes and TiO2 in the fine size range obtained from different commercial sources, was highly variable, implying that composition rather than size was responsible for the oxidant response. A strong chemiluminescence response was not consistently associated with cytotoxicity in the responsive cell. Taken together, these results suggest that oxidant activation by various sources of particulate matter is cell specific. Therefore, the inflamed lung is likely to be more susceptible to harm of ambient air particulates because of the oxidant stress posed by a broader range of particles.
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PMID:Differential particulate air pollution induced oxidant stress in human granulocytes, monocytes and alveolar macrophages. 1202 May 93

Pulmonary particulate matter (PM) exposure has been epidemiologically associated with an increased risk of cardiovascular morbidity and mortality, but the mechanistic foundations for this association are unclear. Exposure to certain types of PM causes changes in the vascular reactivity of several macrovascular segments. However, no studies have focused upon the systemic microcirculation, which is the primary site for the development of peripheral resistance and, typically, the site of origin for numerous pathologies. Ultrafine PM--also referred to as nanoparticles, which are defined as ambient and engineered particles with at least one physical dimension less than 100 nm (Oberdorster et al. 2005)--has been suggested to be more toxic than its larger counterparts by virtue of a larger surface area per unit mass. The purpose of this study was fourfold: (1) determine whether particle size affects the severity of postexposure microvascular dysfunction; (2) characterize alterations in microvascular nitric oxide (NO) production after PM exposure; (3) determine whether alterations in microvascular oxidative stress are associated with NO production, arteriolar dysfunction, or both; and (4) determine whether circulating inflammatory mediators, leukocytes, neurologic mechanisms, or a combination of these play a fundamental role in mediating pulmonary PM exposure and peripheral microvascular dysfunction. To achieve these goals, we created an inhalation chamber that generates stable titanium dioxide (TiO2) aerosols at concentrations up to 20 mg/m3. TiO2 is a well-characterized particle devoid of soluble metals. Sprague Dawley and Fischer 344 (F-344) rats were exposed to fine or nano-TiO2 PM (primary count modes of approximately 710 nm and approximately 100 nm in diameter, respectively) at concentrations of 1.5 to 16 mg/m3 for 4 to 12 hours to produce pulmonary loads of 7 to 150 microg in each rat. Twenty-four hours after pulmonary exposure, the following procedures were performed: the spinotrapezius muscle was prepared for in vivo microscopy, blood samples were taken from an arterial line, and various tissues were harvested for histologic and immunohistochemical analyses. Some rats received a bolus dose of cyclophosphamide 3 days prior to PM exposure to deplete circulating neutrophils and bronchoalveolar lavage (BAL) was performed in separate groups of rats exposed to identical TiO2 loads. No significant differences in BAL fluid composition based on PM size or load were found in these rats. Plasma levels of interleukin (IL)-2, IL-18, IL-13, and growth-related oncogene (GRO) (also known as keratinocyte-derived-chemokine [KC]) were altered after PM exposure. In rats exposed to fine TiO2, endothelium-dependent arteriolar dilation was significantly decreased, and this dysfunction was robustly augmented in rats exposed to nano-TiO2. This effect was not related to an altered smooth-muscle responsiveness to NO because arterioles in both groups dilated comparably in response to the NO donor sodium nitroprusside (SNP). Endogenous microvascular NO production was similarly decreased after inhalation of either fine or nano-TiO2 in a dose-dependent manner. Microvascular oxidative stress was significantly increased among both exposure groups. Furthermore, treatment with antioxidants (2,2,6,6-tetramethylpiperdine-N-oxyl [TEMPOL] plus catalase), the myeloperoxidase (MPO) inhibitor 4-aminobenzoic hydrazide (ABAH), or the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) inhibitor apocynin partially restored NO production and normalized arteriolar function in both groups. Neutrophil depletion restored dilation in PM-exposed rats by as much as 42%. Coincubation of the spinotrapezius muscle with the fast sodium (Na+) channel antagonist tetrodotoxin (TTX) restored arteriolar dilation by as much as 54%, suggesting that sympathetic neural input may be affected by PM exposure. The results of these experiments indicate that (1) the size of inhaled PM dictates the intensity of systemic microvascular dysfunction; (2) this arteriolar dysfunction is characterized by a decreased bioavailability of endogenous NO; (3) the loss of bioavailable NO after PM exposure is at least partially caused by elevations in local oxidative stress, MPO activity, NADPH oxidase activity, or a combination of these responses; and (4) circulating neutrophils and sympathetic neurogenic mechanisms also appear to be involved in the systemic microvascular dysfunction that follows PM exposure. Taken together, these mechanistic studies support prominent hypotheses that suggest peripheral vascular effects associated with PM exposure are due to the activation of inflammatory mechanisms, neurogenic mechanisms, or both.
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PMID:Pulmonary particulate matter and systemic microvascular dysfunction. 2232 39

Titanium dioxide (TiO2) anatase nanoparticles (NPs) are metal oxide NPs commercialized for several uses of everyday life. However their toxicity has been poorly investigated. Cellular internalization of NPs has been shown to activate macrophages and neutrophils that contribute to superoxide anion production by the NADPH oxidase complex. Transmission electron micrososcopy images showed that the membrane fractions were close to the NPs while fluorescence indicated an interaction between NPs and cytosolic proteins. Using a cell-free system, we have investigated the influence of TiO2 NPs on the behavior of the NADPH oxidase. In the absence of the classical activator molecules of the enzyme (arachidonic acid) but in the presence of TiO2 NPs, no production of superoxide ions could be detected indicating that TiO2 NPs were unable to activate by themselves the complex. However once the NADPH oxidase was activated (i.e., by arachidonic acid), the rate of superoxide anion production went up to 140% of its value without NPs, this effect being dependent on their concentration. In the presence of TiO2 nanoparticles, the NADPH oxidase produces more superoxide ions, hence induces higher oxidative stress. This hyper-activation and the subsequent increase in ROS production by TiO2 NPs could participate to the oxidative stress development.
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PMID:Titanium Dioxide Nanoparticles Increase Superoxide Anion Production by Acting on NADPH Oxidase. 2671 8