Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

Rama Malaviya, Alessandro Venosa, Le Roy Hall, Andrew J. Gow, Patrick J. Sinko, Jeffrey D. Laskin, Debra L. Laskin

Результат исследований: Материалы для журналаСтатья

25 Цитирования (Scopus)

Выдержка

Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1d-28d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS+ and cyclooxygenase-2+) and alternatively activated profibrotic (YM-1+ and galectin-3+) macrophages appeared in the lung following NM administration; this was evident within 1d, and persisted for 28d. AG administration (50mg/kg, 2×/day, 1d-3d) abrogated NM-induced injury, oxidative stress and inflammation at 1d and 3d post exposure, with no effects at 7d or 28d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis.

Язык оригиналаАнглийский
Страницы (с-по)279-291
Число страниц13
ЖурналToxicology and Applied Pharmacology
Том265
Номер выпуска3
DOI
СостояниеОпубликовано - 15 дек 2012
Опубликовано для внешнего пользованияДа

Отпечаток

Mechlorethamine
Lung Injury
Nitric Oxide Synthase
Pneumonia
Nitric Oxide Synthase Type II
Lung
Oxidative stress
Oxidative Stress
Bronchoalveolar Lavage Fluid
Toxicity
Wounds and Injuries
Fibrosis
Galectin 3
Alveolar Epithelial Cells
Heme Oxygenase-1
Fluids
Pulmonary Fibrosis
Irritants
Macrophages
Poisons

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Цитировать

Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor. / Malaviya, Rama; Venosa, Alessandro; Hall, Le Roy; Gow, Andrew J.; Sinko, Patrick J.; Laskin, Jeffrey D.; Laskin, Debra L.

В: Toxicology and Applied Pharmacology, Том 265, № 3, 15.12.2012, стр. 279-291.

Результат исследований: Материалы для журналаСтатья

Malaviya, Rama ; Venosa, Alessandro ; Hall, Le Roy ; Gow, Andrew J. ; Sinko, Patrick J. ; Laskin, Jeffrey D. ; Laskin, Debra L. / Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor. В: Toxicology and Applied Pharmacology. 2012 ; Том 265, № 3. стр. 279-291.
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abstract = "Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1d-28d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS+ and cyclooxygenase-2+) and alternatively activated profibrotic (YM-1+ and galectin-3+) macrophages appeared in the lung following NM administration; this was evident within 1d, and persisted for 28d. AG administration (50mg/kg, 2×/day, 1d-3d) abrogated NM-induced injury, oxidative stress and inflammation at 1d and 3d post exposure, with no effects at 7d or 28d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis.",
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T1 - Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

AU - Malaviya, Rama

AU - Venosa, Alessandro

AU - Hall, Le Roy

AU - Gow, Andrew J.

AU - Sinko, Patrick J.

AU - Laskin, Jeffrey D.

AU - Laskin, Debra L.

PY - 2012/12/15

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KW - INOS

KW - Macrophages

KW - Nitric oxide

KW - Oxidative stress

KW - Pulmonary toxicity

KW - Vesicants

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