Cellular and Molecular Characterization of Ozone-Induced Pulmonary Inflammation in the Cynomolgus Monkey

Hicks, Alexandra; Kourteva, Galina; Hilton, Holly; Liu, Hongli; Lin, Teng Nan; Liao, Will; Liu, Ying; Wei, Xin; March, Thomas H.; Benson, Janet M.; Renzetti, Louis M.

doi:10.1007/s10753-009-9168-5

Cited by 12 publications

(5 citation statements)

References 33 publications

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“…Consistent with the reported inflammatory effects of ozone in rhesus monkeys, a recent investigation in adult cynomolgus monkeys also shows that PMNs are the major leukocyte population recruited into the lung following acute ozone exposure (1 ppm/6 h) (23). In the current study, we found that airways inflammation in 6-mo-old monkeys immediately following 5 mo of episodic exposure at 0.5 ppm/8 h is eosinophilic in phenotype.…”

Section: Discussionsupporting

confidence: 91%

Postnatal episodic ozone results in persistent attenuation of pulmonary and peripheral blood responses to LPS challenge

Maniar-Hew

Postlethwait

Fanucchi

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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Early life is a dynamic period of growth for the lung and immune system. We hypothesized that ambient ozone exposure during postnatal development can affect the innate immune response to other environmental challenges in a persistent fashion. To test this hypothesis, we exposed infant rhesus macaque monkeys to a regimen of 11 ozone cycles between 30 days and 6 mo of age; each cycle consisted of ozone for 5 days (0.5 parts per million at 8 h/day) followed by 9 days of filtered air. Animals were subsequently housed in filtered air conditions and challenged with a single dose of inhaled LPS at 1 yr of age. After completion of the ozone exposure regimen at 6 mo of age, total peripheral blood leukocyte and polymorphonuclear leukocyte (PMN) numbers were reduced, whereas eosinophil counts increased. In lavage, total cell numbers at 6 mo were not affected by ozone, however, there was a significant reduction in lymphocytes and increased eosinophils. Following an additional 6 mo of filtered air housing, only monocytes were increased in blood and lavage in previously exposed animals. In response to LPS challenge, animals with a prior history of ozone showed an attenuated peripheral blood and lavage PMN response compared with controls. In vitro stimulation of peripheral blood mononuclear cells with LPS resulted in reduced secretion of IL-6 and IL-8 protein in association with prior ozone exposure. Collectively, our findings suggest that ozone exposure during infancy can result in a persistent effect on both pulmonary and systemic innate immune responses later in life.

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Section: Discussionsupporting

confidence: 91%

Postnatal episodic ozone results in persistent attenuation of pulmonary and peripheral blood responses to LPS challenge

Maniar-Hew

Postlethwait

Fanucchi

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…We have shown that ongoing oxidative damage and inflammation are important in the pathogenesis of progressive pulmonary disease in rodents, and have also documented involvement of the TGF-beta pathway in radiation-induced pulmonary fibrosis in the rat model [ 27 ]. Gene expression studies of the response of primate lungs to ozone-induced oxidative injury also show not only an inflammatory response, with elevations of interleukins 6, 8 and 10, but also a matrix remodeling response, including 3- to 5-fold elevations of matrix metalloproteinase I, metallothionein, and tenascin [ 66 ]. Involvement of TGF beta and matrix remodeling pathways may provide additional preventive or therapeutic targets, in addition to oxidative damage pathways.…”

Section: Discussionmentioning

confidence: 99%

Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation

et al. 2018

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Radiation injury to the lung is the result of acute and chronic free radical formation, and there are currently few effective means of mitigating such injury. Studies in rodents indicate that superoxide dismutase mimetics may be effective in this regard; however, studies in humans or large animals are lacking. We hypothesized that post-exposure treatment with the lipophilic mitochondrial superoxide dismutase mimetic, MnTnHex-2-PyP5+ (hexyl), would reduce radiation-induced pneumonitis and fibrosis in the lungs of nonhuman primates. Rhesus monkeys (Macaca mulatta) received 10 Gy whole thorax irradiation, 10 Gy + hexyl treatment, sham irradiation, or sham irradiation + hexyl. Hexyl was given twice daily, subcutaneously, at 0.05 mg/kg, for 2 months. Animals were monitored daily, and respiratory rates, pulse oximetry, hematology and serum chemistry panels were performed weekly. Computed tomography scans were performed at 0, 2, and 4 months after irradiation. Supportive fluid therapy, corticosteroids, analgesics, and antibiotics were given as needed. All animals were humanely euthanized 4.5 months after irradiation, and pathologic assessments were made. Multifocal, progressive lung lesions were seen at 2 and 4 months in both irradiated groups. Hexyl treatment delayed the onset of radiation-induced lung lesions, reduced elevations of respiratory rate, and reduced pathologic increases in lung weight. No adverse effects of hexyl treatment were found. These results demonstrate (1) development of a nonhuman primate model of radiation-induced lung injury, (2) a significant mitigating effect of hexyl treatment on lung pathology in this model, and (3) no evidence for toxicity of hexyl at the dose studied.

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“…We found that ozone-induced increases in BAL protein were correlated with elevated levels of lipocalin 24p3, an acute phase protein and marker of oxidative stress (Roudkenar et al, 2007; Sunil et al, 2007). Lipocalin 24p3 has been detected in the lung after exposure of rodents to endotoxin or particulate matter, as well as in sputum from patients with chronic obstructive pulmonary disease, and in blood from Cynomolgus monkeys exposed to ozone (Andre et al, 2006; Hicks et al, 2010; Keatings et al, 1997; Sunil et al, 2007; Sunil et al, 2009). Our findings that lipocalin 24p3 is increased in the lung after ozone are novel, and suggest that it may be a sensitive marker of acute oxidant-induced lung injury.…”

Section: Discussionmentioning

confidence: 99%

Ozone-induced lung injury and sterile inflammation. Role of toll-like receptor 4

Connor

Laskin²,

Laskin

2012

Experimental and Molecular Pathology

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Inhalation of toxic doses of ozone is associated with a sterile inflammatory response characterized by an accumulation of macrophages in the lower lung which are activated to release cytotoxic/proinflammatory mediators that contribute to tissue injury. Toll-like receptor 4 (TLR4) is a pattern recognition receptor present on macrophages that has been implicated in sterile inflammatory responses. In the present studies we used TLR4 mutant C3H/HeJ mice to analyze the role of TLR4 in ozone-induced lung injury, oxidative stress and inflammation. Acute exposure of control C3H/HeOuJ mice to ozone (0.8 ppm for 3 hr) resulted in increases in bronchoalveolar lavage (BAL) lipocalin 24p3 and 4-hydroxynonenal modified protein, markers of oxidative stress and lipid peroxidation. This was correlated with increases in BAL protein, as well as numbers of alveolar macrophages. Levels of surfactant protein-D, a pulmonary collectin known to regulate macrophage inflammatory responses also increased in BAL following ozone inhalation. Ozone inhalation was associated with classical macrophage activation, as measured by increased NF-κB binding activity and expression of TNFα mRNA. The observation that these responses to ozone were not evident in TLR4 mutant C3H/HeJ mice demonstrates that functional TLR4 contributes to ozone-induced sterile inflammation and macrophage activation.

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Cellular and Molecular Characterization of Ozone-Induced Pulmonary Inflammation in the Cynomolgus Monkey

Cited by 12 publications

References 33 publications

Postnatal episodic ozone results in persistent attenuation of pulmonary and peripheral blood responses to LPS challenge

Postnatal episodic ozone results in persistent attenuation of pulmonary and peripheral blood responses to LPS challenge

Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation

Ozone-induced lung injury and sterile inflammation. Role of toll-like receptor 4

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