Induced Production of Nitric Oxide, Tumor Necrosis Factor, and Interleukin-6 in RAW 264.7 Macrophages by Streptomycetes from Indoor Air of Moldy Houses

Hirvonen, Maija-Riitta; Nevalainen, Aino; Makkonen, Niina; Mönkkönen, Jukka; Savolainen, Kai

doi:10.1080/00039899709602221

Cited by 38 publications

(26 citation statements)

References 28 publications

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“…These results corroborated our in vitro findings, which demonstrated that the spores of streptomycetes effectively induced mouse RAW264.7 macrophages to produce proinflammatory mediators (TNF-␣, IL-6, IL-1, and NO) (10)(11)(12). Individuals in moisture-damaged buildings usually experience repeated exposures to relatively low doses of the spores, and thus, it seemed of interest to study the responses caused by repeated exposures to the spores over a wide dose range in vivo.…”

supporting

confidence: 77%

“…The strain, encoded strain A4 in our previous in vitro studies (10)(11)(12), was identified by the Deutsche Sammlung von Mikroorganismen und Zellkulturen (Braunschweig, Germany) identification service. The microbe was cultured on Tryptone yeast-glucose agar (Bacto Plate Count Agar; Difco Laboratories, Detroit, Mich.) and incubated at 20°C in the dark for about 5 days.…”

Section: Materials and Methods Exposuresmentioning

confidence: 99%

“…LDH, which is an indicator of cytotoxicity, increased in BALF concomitantly with the albumin and total protein concentrations. The spores of S. californicus are also not highly toxic to mouse RAW264.7 macrophages in vitro (10)(11)(12), and clear cytotoxicity was evident only after a single high dose of 3 ϫ 10 8 spores in mice (20).…”

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confidence: 99%

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Systemic Immunoresponses in Mice after Repeated Exposure of Lungs to Spores of Streptomyces californicus

Jussila

Pelkonen

Kosma

et al. 2003

Clin Vaccine Immunol

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Microbial growth in moisture-damaged buildings is associated with respiratory and other symptoms in the occupants. Streptomyces spp. are frequently isolated from such buildings. In the present study, we evaluated the responses of mice after repeated exposure to spores of Streptomyces californicus. Mice were exposed via intratracheal instillation to six doses (at 7-day intervals) of the spores of S. californicus, originally isolated from the indoor air of a moisture-damaged building, at three dose levels (2 ؋ 10 3 , 2 ؋ 10 5 , and 2 ؋ 10 7 spores). Inflammation and toxicity, including changes in cell populations in the lungs, lymph nodes, and spleen, were evaluated 24 h after the last dosage. The exposure provoked a dose-dependent inflammatory cell response, as detected by the intense recruitment of neutrophils, but the numbers of macrophages and lymphocytes in the airways also increased. The cellular responses corresponded to the dose-dependent increases in inflammationand cytotoxicity-associated biochemical markers (i.e., levels of albumin, total protein, and lactate dehydrogenase) in bronchoalveolar lavage fluid. The spore exposure increased the number of both activated and nonactivated T lymphocytes. Also, the amounts of CD3 ؊ CD4 ؊ and unconventional CD3 ؊ CD4 ؉ lymphocytes in the lung tissue were augmented. Interestingly, the spore exposure decreased cells in the spleen. This effect was strongest at the dose of 2 ؋ 10 5 spores. These results indicate that the spores of S. californicus are capable of provoking both immunostimulation in lungs (inflammation) and systemic immunotoxicity, especially in the spleen. The immunotoxic effect resembled that caused by chemotherapeutic agents, originally isolated from Streptomyces spp. Thus, S. californicus must be considered a microbial species with potential to cause systemic adverse health effects in occupants of moisture-damaged buildings.Microbial growth subsequent to moisture damage in buildings has been connected to increased adverse respiratory and other harmful health effects (7,32,33,37,38,44). Increased numbers of microbial spores are present in the indoor air of moisture-damaged buildings (15,16,27). Moreover, several of the microbial species that are frequently detected in moisturedamaged buildings are rarely observed in reference buildings (34). The spores are inhaled deeply into the lungs due to their relatively small particle size (23). Since the spores may also deliver nonvolatile microbial toxins into the lungs (36), they presumably play a role in provoking adverse health effects.Streptomyces californicus is a sporulating gram-positive bacterium that is used as a moisture indicator and that is frequently isolated from the indoor air of moisture-damaged buildings (27,34). Streptomycetes have the genetic capability to produce many bioactive secondary metabolites, such as antibiotics, immunosuppressive agents, antitumor substances, and inhibitors of Ca 2ϩ -and calmodulin-dependent cyclic nucleotide phosphodiesterases, which are important enzymes involved ...

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supporting

confidence: 77%

Section: Materials and Methods Exposuresmentioning

confidence: 99%

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Systemic Immunoresponses in Mice after Repeated Exposure of Lungs to Spores of Streptomyces californicus

Jussila

Pelkonen

Kosma

et al. 2003

Clin Vaccine Immunol

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“…NO in the supernatant was assayed by the Griess reaction as the stable NO oxidation product nitrite [14], as described earlier [15]. Expression of iNOS in the cells of NAL was determined with Western blot analysis [15] with minor modifications.…”

Section: Nitric Oxide Analysismentioning

confidence: 99%

“…Expression of iNOS in the cells of NAL was determined with Western blot analysis [15] with minor modifications.…”

Section: Nitric Oxide Analysismentioning

confidence: 99%

Inflammatory mediators in nasal lavage, induced sputum and serum of employees with rheumatic and respiratory disorders

Roponen

Seuri

et al. 2001

Eur Respir J

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Inflammatory mediators in nasal lavage, induced sputum and serum of employees with rheumatic and respiratory disorders. M. Roponen, J. Kiviranta, M. Seuri, H. Tukiainen, R. Myllykangas-Luosujärvi, M-R. Hirvonen. #ERS Journals Ltd 2001. ABSTRACT: Exposure to microbes present in mould-damaged buildings has been linked to increased frequency of various inflammatory diseases. The current study examined differences in inflammatory mediators in nasal lavage (NAL), induced sputum (IS) and serum of occupants with rheumatic or respiratory disorders and their controls, all working in the same moisture-damaged building.Exhaled nitric oxide (NO) measurements, lung function tests, skin-prick tests and health data collection by questionnaire were performed. Concentrations of NO, interleukin (IL)-1, IL-4, IL-6 and tumour necrosis factor-a in NAL, IS and serum (excluding NO and IL-1) of the subjects were measured during an occupational exposure period and the vacation period without such exposure.The concentrations of IL-4 in NAL fluid were significantly higher among all occupants during the working period (geometric mean 8.5 pg?mL -1 , range 0-206.5 pg?mL -1 ), as compared to that during vacation (0.4 pg?mL -1 , range 0-3.7 pg?mL -1 ) (p=0.008). Absence from the work environment also significantly diminished reporting of symptoms. IL-4 levels in the serum of case subjects were significantly higher than in controls. Moreover, employees with respiratory symptoms had markedly higher exhaled NO values than their controls (p=0.028).In summary, these data suggest that mediators in nasal lavage samples reflect the occupational exposure to moulds, whereas possible indicators of existing disorders are detectable in serum.

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Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms

Pall

2009

General, Applied and Systems Toxicology

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Cases of multiple chemical sensitivity (MCS) are initiated by exposure to organic solvents and three classes of pesticides. Each of these can act indirectly to increase NMDA activity and the toxic effects of members of each of these classes can be lowered by using NMDA antagonists. Other chemicals, mercury, H 2 S and CO exposure may also initiate cases of MCS and have toxic responses mediated through increased NMDA activity. Thus each of these types of chemicals appears to act as a toxicant through increased NMDA activity. Six additional types of evidence suggest roles for elevated NMDA activity in MCS, suggesting that this response is involved, not only in MCS case initiation, but also in response to low‐level chemicals in those who are already sensitive. The inference that chemicals act as toxicants in MCS is confirmed by three genetic studies showing that five genes that encode enzymes that metabolize these chemicals act to determine MCS susceptibility. The chronic nature of MCS is thought to be produced by a local biochemical vicious cycle mechanism, the NO/ONOO − cycle, which is initiated by nitric oxide acting through its oxidant product peroxynitrite, which are both produced in MCS in response to excessive NMDA activity. Cycle elements, including NMDA activity, intracellular calcium, nitric oxide and peroxynitrite are thought to interact with other mechanisms, including neural sensitization in the brain and neurogenic inflammation in peripheral tissues to produce the high‐level chemical sensitivity that is the hallmark of MCS. This complex model of MCS is supported by the following types of observations: MCS correlates in the chronic phase of illness, extensive animal model studies implicating almost all NO/ONOO − cycle elements, clinical trial data in the related illnesses chronic fatigue syndrome and fibromyalgia, and a variety of objectively measurable responses to low‐level chemical exposure in MCS patients, responses that should be further studied as possible specific biomarker tests for MCS. While plausible mechanisms are proposed for the generation of both shared and specific symptoms and signs in MCS, there are little data on whether these mechanisms are actually involved in generating these symptoms and signs in MCS. Previous claims that MCS is produced by some sort of psychogenic mechanism have multiple flaws and are inconsistent with the various types of evidence discussed above. Several areas of research are discussed in which the author argues that research will be richly rewarded.

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Induced Production of Nitric Oxide, Tumor Necrosis Factor, and Interleukin-6 in RAW 264.7 Macrophages by Streptomycetes from Indoor Air of Moldy Houses

Cited by 38 publications

References 28 publications

Systemic Immunoresponses in Mice after Repeated Exposure of Lungs to Spores of Streptomyces californicus

Systemic Immunoresponses in Mice after Repeated Exposure of Lungs to Spores of Streptomyces californicus

Inflammatory mediators in nasal lavage, induced sputum and serum of employees with rheumatic and respiratory disorders

Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms

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