metallothionein and Pneumonia

The integration of knowledge concerning the regulation of metallothionein (MT) with research on its proposed functions is necessary to clarify how MT affects cellular processes. MT expression is induced/enhanced in various tissues by a number of physiological mediators through several response elements in the MT gene promoter. The cellular accumulation of MT depends on the availability of cellular zinc derived from the diet. MT modulates: 1) the binding and exchange/ transport of heavy metals such as zinc, cadmium, or copper under physiological conditions and cytoprotection from their toxicities, and 2) the release of gaseous mediators such as hydroxyl radicals or nitric oxide. In addition, MT reportedly affects a number of cellular processes, such as gene expression, apoptosis, proliferation, and differentiation. Given the genetic approach, the apparently healthy status of MT-deficient mice argues against an essential biological role for MT; however, the molecule may be critical in cells/tissues/organs in times of stress, since MT expression is also evoked/enhanced by various stresses. In particular, because metallothionein (MT) is induced by inflammatory stress, its roles in inflammation are implied. Also, MT expression in the lung can be enhanced by inflammatory stimuli, suggesting that its expression correlates with inflammatory pulmonary diseases. In this paper, we review the role of MT of various inflammatory conditions in the airway.

Topics: Animals; Gene Expression Regulation; Humans; Metallothionein; Pneumonia

It is known that inhalation of zinc oxide nanoparticles (ZnO NPs) induces acute pulmonary dysfunction, including oxidative stress, inflammation, and injury, but there are no reports on how to prevent these adverse effects. We have previously reported that the pulmonary symptoms caused by ZnO NPs were associated with oxidative stress; in the present study, we therefore investigated the use of ascorbic acid (AA), which is known as vitamin C, to prevent these toxic effects.. A ZnO NP dispersion was introduced into rat lungs by intratracheal injection, and thereafter a 1% aqueous AA solution was given as drinking water. Bronchoalveolar lavage fluid was collected at 1 day and 1 week after injection, and lactate dehydrogenase (LDH) activity, heme oxygenase-1 (HO-1), and interleukin-6 (IL-6) levels were measured. In addition, expression of the chemokine cytokine-induced neutrophil chemoattractants (CINCs), HO-1, and metallothionein-1 (MT-1) genes in the lungs were determined.. Acute oxidative stress induced by ZnO NPs was suppressed by supplying AA. Increases in LDH activity and IL-6 concentration were also suppressed by AA, as was the expression of the CINC-1, CINC-3, and HO-1 genes.. Oral intake of AA prevents acute pulmonary oxidative stress and inflammation caused by ZnO NPs. Intake of AA after unanticipated exposure to ZnO NPs is possibly the first effective treatment for the acute pulmonary dysfunction they cause.

Topics: Animals; Antioxidants; Ascorbic Acid; Bronchoalveolar Lavage Fluid; Chemokine CXCL1; Heme Oxygenase-1; Inhalation Exposure; Interleukin-6; Lactate Dehydrogenases; Lung; Male; Metallothionein; Nanoparticles; Oxidative Stress; Pneumonia; Rats; Rats, Wistar; Zinc Oxide

Chamber studies in adult humans indicate reduced responses to acute ozone with increasing age. Age-related changes in TNFα have been observed. TNFα induced inflammation is predominantly mediated through TNFR1.. To examine the impact of aging on inflammatory responses to acute ozone exposure in mice and determine the role of TNFR1 in age-related differences.. Wildtype and TNFR1 deficient (TNFR1(-/-)) mice aged 7 or 39 weeks were exposed to ozone (2 ppm for 3 h). Four hours after exposure, bronchoalveolar lavage (BAL) was performed and BAL cells, cytokines, chemokines, and protein were examined.. Ozone-induced increases in BAL neutrophils and in neutrophil chemotactic factors were lower in 39- versus 7-week-old wildtype, but not (TNFR1(-/-)) mice. There was no effect of TNFR1 genotype in 7-week-old mice, but in 39-week-old mice, BAL neutrophils and BAL concentrations of MCP-1, KC, MIP-2, IL-6 and IP-10 were significantly greater following ozone exposure in TNFR1(-/-) versus wildtype mice. BAL concentrations of the soluble form of the TNFR1 receptor (sTNFR1) were substantially increased in 39-week-old versus 7-week-old mice, regardless of exposure.. The data suggest that increased levels of sTNFR1 in the lungs of the 39-week-old mice may neutralize TNFα and protect these older mice against ozone-induced inflammation.

Topics: Aging; Amphiregulin; Animals; Bronchoalveolar Lavage Fluid; Claudin-4; Claudins; Cytokines; EGF Family of Proteins; Female; Gene Expression; Glycoproteins; Heme Oxygenase-1; Intercellular Signaling Peptides and Proteins; Leukocyte Count; Male; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Oxidants, Photochemical; Ozone; Pneumonia; Receptors, Tumor Necrosis Factor, Type I; RNA, Messenger

Metallothionein (MT) is a free radical scavenger induced by inflammatory stimuli; however, its roles in inflammation have not been fully investigated. In the present study, we genetically determined the role of MT in ozone (O(3))-induced lung inflammation using MT-I/II null (-/-) mice. Subacute (65 h) exposure to O(3) (0.3 ppm) induced lung inflammation and enhanced vascular permeability, which was significantly greater in MT(-/-) than in corresponding wild-type mice. Electron microscopically, O(3) exposure induced vacuolar degeneration of pulmonary endothelial and epithelial cells, and interstitial edema with focal loss of the basement membrane, which was more prominent in MT(-/-) than in wild-type mice. O(3) -induced lung expression of interleukin-6 was significantly greater in MT(-/-) than in wild-type mice; however, lung expression of the chemokines examined was comparable in both genotypes of mice in the presence of O(3). Following O(3) exposure, the formation of oxidative stress-related molecules/adducts, such as heme oxidase-1, inducible nitric oxide synthase, 8-hydroxy-2'-deoxyguanosine, and nitrotyrosine, in the lung was significantly greater in MT(-/-) than in wild-type mice. Collectively, MT protects against O(3)-induced lung inflammation, at least partly, via the regulation of pulmonary endothelial and epithelial integrity and its antioxidative property.

Topics: Animals; Bronchoalveolar Lavage Fluid; Chemokines; Cytokines; Female; Heme Oxygenase-1; Immunoenzyme Techniques; Lipopolysaccharides; Macrophages, Alveolar; Male; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type II; Oxidants, Photochemical; Ozone; Pneumonia; Respiratory Function Tests; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

There is sufficient evidence for pulmonary carcinogenicity of inhaled Cd compounds in rats whereas no such evidence was found in mice and hamsters; the evidence in humans has been termed limited, indicating significant species differences in pulmonary response to inhaled Cd. We hypothesized that expression of metallothionein (MT) protein in the lung after inhalation of Cd differs between species thereby providing different degrees of sequestration of Cd and protection from its effects. Rats and mice were exposed to 100 micrograms CdCl2 aerosols/m3 for 4 weeks, and the presence of MT was determined in lung and free lung cell homogenates as well as by immunocytochemistry in lung sections up to 28 days postexposure. In addition, pulmonary inflammatory, and cell proliferative responses were determined. Cd exposure significantly increased MT in homogenates of total lung in both species; however, no significant increase of MT in rat lung tissue after removal of free lung cells by lavage was found whereas MT was still significantly increased in lavaged mouse lung tissue throughout the postexposure time. In contrast, exposed rats showed significant increases in MT in the lavageable lung cells and mice did not. Histochemical analysis of lung sections revealed that mainly the epithelial cells of the bronchi, bronchioli, and alveoli of Cd-exposed mice expressed MT. Mice also exhibited a marked and sustained pulmonary inflammatory and cell proliferative response upon CdCl2 exposure which was not observed in rats. The retained Cd dose per gram lung was about 2-fold greater in mice, which is consistent with a greater deposition efficiency of inhaled Cd-aerosols in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Inhalation; Animals; Cadmium; Carcinogens; Humans; Lung Diseases; Male; Metallothionein; Mice; Pneumonia; Rats; Rats, Inbred F344; Species Specificity

Pulmonary clearance and toxicity of cupric oxide (CuO) dusts, which are probably formed in refining and smelting factories, were investigated. Groups of three rats received intratracheal (i.t.) instillation of CuO at a dose of 20 micrograms Cu/rat in time-course experiments (up to 7 days post-instillation). Other groups of three rats received i.t. instillation of CuO at doses of 2.5, 5, 10, 30, 50 and 100 micrograms Cu/rat and were killed at 2 days post-instillation in dose-effect experiments. Intratracheally instilled CuO particles were cleared from the lung with a half-time of 37 h. Copper binding metallothionein (MT) was induced in a dose-dependent manner and detected at 12 h to 3 days post-instillation. Rapid clearance of CuO from the lung and induction of MT at 12 h post-instillation suggest that CuO particles were solubilized and then cleared from the lung. The acute pulmonary toxicity of CuO was evaluated by cytological (numbers of macrophages and polymorphonuclear leukocytes), biochemical and elemental inflammatory indices (lactate dehydrogenase and beta-glucuronidase activities and protein, sulfur, phosphorus and calcium contents) in the bronchoalveolar lavage (BAL) fluid. These inflammatory indices peaked at 12 h to 3 days post-instillation, and increased with dose over the dose range, except for phosphorus content. Dose-effect relationships in BAL inflammatory indicators of CuO-injected (i.t.) groups were compared to those of CuSO4-injected (i.t.) groups. The results of the comparison indicated that there was no significant difference in acute inflammatory potency between CuSO4 (soluble form of Cu) and CuO (insoluble form of Cu) in the rat lung.

Topics: Air Pollutants, Occupational; Animals; Bronchoalveolar Lavage Fluid; Copper; Copper Sulfate; Dust; Intubation, Intratracheal; Lung; Male; Metallothionein; Organ Size; Pneumonia; Rats; Rats, Wistar

Though copper (Cu)-handling workers are known to be at risk to develop metal fume fever and acute respiratory failure, very little is known about the metabolic fate and pulmonary toxicity of Cu compounds deposited in the lung. We have investigated time-course and dose-related changes in Cu contents, the production of metallothionein (MT) and inflammatory responses in the rat lung following intratracheal instillation of cupric sulfate (CuSO4). Intratracheally instilled Cu was cleared rapidly from the lung with a half-time of 7.5 h. Copper-binding MT was induced in the lung tissue following Cu instillation and the amount of MT increased with the dose of CuSO4. However, the production of MT contributed little to the accumulation of Cu in the lung. The pulmonary toxicity of CuSO4 was evaluated by examining time-course and dose-effect profiles of cytological and biochemical inflammatory indices (enzymes, protein and elements) retrieved in bronchoalveolar lavage fluids. These results revealed that the inflammatory indices reached maximum values in their activities and contents at 12 h to 3 days after instillation and a dose of 5 micrograms Cu/rat was sufficient to produce acute inflammatory responses in the rat lung.

Topics: Animals; Bronchoalveolar Lavage Fluid; Calcium; Chromatography, High Pressure Liquid; Copper; Copper Sulfate; Half-Life; Lung; Male; Metallothionein; Phosphorus; Pneumonia; Rats; Rats, Inbred Strains; Sulfur; Tissue Distribution