Attenuation of ozone-induced lung injury by interleukin-10

Reinhart, Paul G.; Gupta, Suresh; Bhalla, Deepak K.

doi:10.1016/s0378-4274(99)00136-8

Cited by 21 publications

(14 citation statements)

References 26 publications

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“…In accord with previous studies we found that ozone inhalation resulted in decreased IL-10 expression in the lungs of wild-type mice (27). IL-10 is known to suppress IB kinase and inhibit NF-B DNA binding activity, thus limiting the generation of potentially toxic inflammatory mediators (29).…”

Section: Discussionsupporting

confidence: 92%

Ozone-induced production of nitric oxide and TNF-α and tissue injury are dependent on NF-κB p50

Fakhrzadeh

Laskin²,

Laskin³

2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Ozone-induced lung injury is associated with increased production of reactive nitrogen intermediates and TNF-alpha, which have been implicated in the pathogenic process. Generation of these mediators is regulated in part by transcription factors, e.g., NF-kappaB and CCAAT/enhancer-binding protein (C/EBP). The present studies used NF-kappaB p50 knockout mice to assess the role of this transcription factor protein in ozone-induced inflammatory mediator production and toxicity. Treatment of wild-type (WT) mice with ozone (0.8 ppm, 3 h) resulted in a rapid increase in NF-kappaB binding activity in alveolar macrophages that peaked after 6-12 h. This response was attenuated in NF-kappaB p50(-)/(-) mice. In WT mice, but not NF-kappaB p50(-)/(-) mice, C/EBP was also markedly increased in macrophages following ozone inhalation. Ozone also induced changes in the mobility of C/EBP in gel shift assays, suggesting alterations in the transcription factor complex that may be important in controlling inflammatory gene expression. Whereas macrophages from WT mice produced increased quantities of nitric oxide and TNF-alpha following ozone inhalation, this was not observed in cells from NF-kappaB p50(-)/(-) mice. Ozone-induced decreases in expression of the anti-inflammatory cytokine IL-10 were also prevented in NF-kappaB p50(-)/(-) mice. In WT mice, ozone inhalation caused an increase in bronchoalveolar lavage protein, a marker of tissue damage. This was not evident in NF-kappaB p50(-)/(-) mice. There was also no evidence of peroxynitrite-mediated lung injury in these mice. These findings demonstrate that NF-kappaB and possibly C/EBP signaling are important in ozone-induced production of reactive nitrogen intermediates and TNF-alpha and in tissue injury.

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Section: Discussionsupporting

confidence: 92%

Ozone-induced production of nitric oxide and TNF-α and tissue injury are dependent on NF-κB p50

Fakhrzadeh

Laskin²,

Laskin³

2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Interestingly, Reinhart et al (1999) found that intratracheal instillation of recombinant IL-10 into Sprague-Dawley rats significantly attenuated by 25% protein permeability responses induced by acute O 3 exposure (0.8 ppm, 3 hr) compared with controls. An explanation for the disparate observations is not entirely clear, but the role of IL-10 in the hyperpermeability response may depend on the concentration and duration of exposure to O 3 (0.8 ppm for 3 hr compared with 0.3 ppm for 24, 48, or 72 hr) or may be species specific.…”

Section: Discussionmentioning

confidence: 96%

“…IL-10 reduces TNF-α and IL-6 production (Lang et al 2002), and inhibits MIP-2 (Standiford et al 1995). Previously, Reinhart et al (1999) showed that intratracheal instillation of recombinant IL-10 in Sprague-Dawley rats before O 3 exposure significantly reduced O 3 -induced PMN infiltration and pulmonary hyperpermeability responses [fibronectin, albumin, bronchoalveolar lavage fluid (BALF) protein]. However, the relationship between IL-10 and other inflammatory mediators and downstream molecular events has not been investigated.…”

mentioning

confidence: 99%

Protective Role of Interleukin-10 in Ozone-Induced Pulmonary Inflammation

Backus

Howden

Fostel

et al. 2010

Environ Health Perspect

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BackgroundThe mechanisms underlying ozone (O3)-induced pulmonary inflammation remain unclear. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators.ObjectivesWe investigated the molecular mechanisms underlying interleuken-10 (IL-10)–mediated attenuation of O3-induced pulmonary inflammation in mice.MethodsIl10-deficient (Il10−/−) and wild-type (Il10+/+) mice were exposed to 0.3 ppm O3 or filtered air for 24, 48, or 72 hr. Immediately after exposure, differential cell counts and total protein (a marker of lung permeability) were assessed from bronchoalveolar lavage fluid (BALF). mRNA and protein levels of cellular mediators were determined from lung homogenates. We also used global mRNA expression analyses of lung tissue with Ingenuity Pathway Analysis to identify patterns of gene expression through which IL-10 modifies O3-induced inflammation.ResultsMean numbers of BALF polymorphonuclear leukocytes (PMNs) were significantly greater in Il10−/− mice than in Il10+/+ mice after exposure to O3 at all time points tested. O3-enhanced nuclear NF-κB translocation was elevated in the lungs of Il10−/− compared with Il10+/+ mice. Gene expression analyses revealed several IL-10–dependent and O3-dependent mediators, including macrophage inflammatory protein 2, cathepsin E, and serum amyloid A3.ConclusionsResults indicate that IL-10 protects against O3-induced pulmonary neutrophilic inflammation and cell proliferation. Moreover, gene expression analyses identified three response pathways and several genetic targets through which IL-10 may modulate the innate and adaptive immune response. These novel mechanisms of protection against the pathogenesis of O3-induced pulmonary inflammation may also provide potential therapeutic targets to protect susceptible individuals.

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“…This is supported by findings that blocking proinflammatory macrophages or cytotoxic mediators they release protects against ozone-induced lung injury (Pendino et al , 1995; Kleeberger et al , 2001; Fakhrzadeh et al , 2002; Toward and Broadley, 2002; Fakhrzadeh et al , 2004a; Fakhrzadeh et al , 2004b). Macrophages have also been shown to play a protective role in the lung following ozone exposure, clearing oxidized products and cellular debris (Ishii et al , 1998; Dahl et al , 2007), augmenting lung antioxidant activity, and releasing mediators that suppress inflammation and initiate wound repair (Reinhart et al , 1999; Dahl et al , 2007; Backus et al , 2010). These activities are mediated by distinct subpopulations of macrophages that are alternatively activated (Byers and Holtzman, 2011; Laskin et al , 2011).…”

Section: Introductionmentioning

confidence: 99%

Regulation of ozone-induced lung inflammation and injury by the β-galactoside-binding lectin galectin-3

Sunil

Francis

Vayas

et al. 2015

Toxicology and Applied Pharmacology

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Macrophages play a dual role in ozone toxicity, contributing to both pro- and anti-inflammatory processes. Galectin-3 (Gal-3) is a lectin known to regulate macrophage activity. Herein, we analyzed the role of Gal-3 in the response of lung macrophages to ozone. Bronchoalveolar lavage (BAL) and lung tissue were collected 24–72 h after exposure (3 h) of WT and Gal-3−/− mice to air or 0.8 ppm ozone. In WT mice, ozone inhalation resulted in increased numbers of proinflammatory (Gal-3+, iNOS+) and anti-inflammatory (MR-1+) macrophages in the lungs. While accumulation of iNOS+ macrophages was attenuated in Gal-3−/− mice, increased numbers of enlarged MR-1+ macrophages were noted. This correlated with increased numbers of macrophages in BAL. Flow cytometric analysis showed that these cells were CD11b+ and consisted mainly (>97%) mature (F4/80+CD11c+) proinflammatory (Ly6G−Ly6Chi) and anti-inflammatory (Ly6G−Ly6Clo) macrophages. Increases in both macrophage subpopulations were observed following ozone inhalation. Loss of Gal-3 resulted in a decrease in Ly6Chi macrophages, with no effect on Ly6Clo macrophages. CD11b+Ly6G+Ly6C+ granulocytic (G) and monocytic (M) myeloid derived suppressor cells (MDSC) were also identified in the lung after ozone. In Gal-3−/− mice, the response of G-MDSC to ozone was attenuated, while the response of M-MDSC was heightened. Changes in inflammatory cell populations in the lung of ozone treated Gal-3−/− mice were correlated with reduced tissue injury as measured by cytochrome b5 expression. These data demonstrate that Gal-3 plays a role in promoting proinflammatory macrophage accumulation and toxicity in the lung following ozone exposure.

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Attenuation of ozone-induced lung injury by interleukin-10

Cited by 21 publications

References 26 publications

Ozone-induced production of nitric oxide and TNF-α and tissue injury are dependent on NF-κB p50

Ozone-induced production of nitric oxide and TNF-α and tissue injury are dependent on NF-κB p50

Protective Role of Interleukin-10 in Ozone-Induced Pulmonary Inflammation

Regulation of ozone-induced lung inflammation and injury by the β-galactoside-binding lectin galectin-3

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