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Nitric oxide-dependent activation of p53 suppresses bleomycin-induced apoptosis in the lung.

Davis DW, Weidner DA, Holian A, McConkey DJ - J. Exp. Med. (2000)

Bottom Line: The effects of bleomycin were associated with translocation of p53 from the cytosol to the nucleus only in alveolar macrophages that had been exposed to the drug in vivo, suggesting that the lung microenvironment regulated p53 activation.A specific role for NO was demonstrated in experiments with inducible nitric oxide synthase (iNOS)(-/)- macrophages, which failed to demonstrate nuclear p53 localization after in vivo bleomycin exposure.Together, our results demonstrate that iNOS and p53 mediate a novel apoptosis-suppressing pathway in the lung.

View Article: PubMed Central - PubMed

Affiliation: Program in Toxicology, University of Texas-Houston Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.

ABSTRACT
Chronic inflammation leading to pulmonary fibrosis develops in response to environmental pollutants, radiotherapy, or certain cancer chemotherapeutic agents. We speculated that lung injury might be mediated by p53, a proapoptotic transcription factor widely implicated in the response of cells to DNA damage. Intratracheal administration of bleomycin led to caspase-mediated DNA fragmentation characteristic of apoptosis. The effects of bleomycin were associated with translocation of p53 from the cytosol to the nucleus only in alveolar macrophages that had been exposed to the drug in vivo, suggesting that the lung microenvironment regulated p53 activation. Experiments with a thiol antioxidant (N-acetylcysteine) in vivo and nitric oxide (NO) donors in vitro confirmed that reactive oxygen species were required for p53 activation. A specific role for NO was demonstrated in experiments with inducible nitric oxide synthase (iNOS)(-/)- macrophages, which failed to demonstrate nuclear p53 localization after in vivo bleomycin exposure. Strikingly, rates of bleomycin-induced apoptosis were at least twofold higher in p53(-/)- C57BL/6 mice compared with heterozygous or wild-type littermates. Similarly, levels of apoptosis were also twofold higher in the lungs of iNOS(-/)- mice than were observed in wild-type controls. Consistent with a role for apoptosis in chronic lung injury, levels of bleomycin-induced inflammation were substantially higher in iNOS(-/)- and p53(-/)- mice compared with wild-type controls. Together, our results demonstrate that iNOS and p53 mediate a novel apoptosis-suppressing pathway in the lung.

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Increased bleomycin-induced inflammation in iNOS−/− and p53−/− mice. Animals were treated with 2.5 U/kg bleomycin via intratracheal administration. At the times indicated, animals were killed and inflammation was assessed by histological analysis after hematoxylin and eosin staining. Note profound inflammatory infiltrate by 7 d in the iNOS- and p53-deficient lungs. Indistinguishable results were observed in each of two animals at each time point.
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Figure 9: Increased bleomycin-induced inflammation in iNOS−/− and p53−/− mice. Animals were treated with 2.5 U/kg bleomycin via intratracheal administration. At the times indicated, animals were killed and inflammation was assessed by histological analysis after hematoxylin and eosin staining. Note profound inflammatory infiltrate by 7 d in the iNOS- and p53-deficient lungs. Indistinguishable results were observed in each of two animals at each time point.

Mentions: Our overall hypothesis is that impaired clearance of apoptotic debris serves as a trigger for inflammation in the early stages of lung injury. This hypothesis predicts that levels of inflammation would be substantially higher in the iNOS−/− and p53−/− mice compared with wild-type controls because of increased cell death. Consistent with this idea, chronic exposure to bleomycin led to marked increases in inflammatory infiltrate and disruption of alveolar architecture in the iNOS−/− and p53−/− mice compared with wild-type littermates (Fig. 9). Increased inflammation was obvious by 7 d after exposure and persisted up to 14 d, at which point the iNOS−/− and p53−/− mice died with high frequency (Fig. 9, and data not shown). These data strongly support roles for iNOS and p53 in suppressing inflammation in this model system.


Nitric oxide-dependent activation of p53 suppresses bleomycin-induced apoptosis in the lung.

Davis DW, Weidner DA, Holian A, McConkey DJ - J. Exp. Med. (2000)

Increased bleomycin-induced inflammation in iNOS−/− and p53−/− mice. Animals were treated with 2.5 U/kg bleomycin via intratracheal administration. At the times indicated, animals were killed and inflammation was assessed by histological analysis after hematoxylin and eosin staining. Note profound inflammatory infiltrate by 7 d in the iNOS- and p53-deficient lungs. Indistinguishable results were observed in each of two animals at each time point.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193293&req=5

Figure 9: Increased bleomycin-induced inflammation in iNOS−/− and p53−/− mice. Animals were treated with 2.5 U/kg bleomycin via intratracheal administration. At the times indicated, animals were killed and inflammation was assessed by histological analysis after hematoxylin and eosin staining. Note profound inflammatory infiltrate by 7 d in the iNOS- and p53-deficient lungs. Indistinguishable results were observed in each of two animals at each time point.
Mentions: Our overall hypothesis is that impaired clearance of apoptotic debris serves as a trigger for inflammation in the early stages of lung injury. This hypothesis predicts that levels of inflammation would be substantially higher in the iNOS−/− and p53−/− mice compared with wild-type controls because of increased cell death. Consistent with this idea, chronic exposure to bleomycin led to marked increases in inflammatory infiltrate and disruption of alveolar architecture in the iNOS−/− and p53−/− mice compared with wild-type littermates (Fig. 9). Increased inflammation was obvious by 7 d after exposure and persisted up to 14 d, at which point the iNOS−/− and p53−/− mice died with high frequency (Fig. 9, and data not shown). These data strongly support roles for iNOS and p53 in suppressing inflammation in this model system.

Bottom Line: The effects of bleomycin were associated with translocation of p53 from the cytosol to the nucleus only in alveolar macrophages that had been exposed to the drug in vivo, suggesting that the lung microenvironment regulated p53 activation.A specific role for NO was demonstrated in experiments with inducible nitric oxide synthase (iNOS)(-/)- macrophages, which failed to demonstrate nuclear p53 localization after in vivo bleomycin exposure.Together, our results demonstrate that iNOS and p53 mediate a novel apoptosis-suppressing pathway in the lung.

View Article: PubMed Central - PubMed

Affiliation: Program in Toxicology, University of Texas-Houston Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.

ABSTRACT
Chronic inflammation leading to pulmonary fibrosis develops in response to environmental pollutants, radiotherapy, or certain cancer chemotherapeutic agents. We speculated that lung injury might be mediated by p53, a proapoptotic transcription factor widely implicated in the response of cells to DNA damage. Intratracheal administration of bleomycin led to caspase-mediated DNA fragmentation characteristic of apoptosis. The effects of bleomycin were associated with translocation of p53 from the cytosol to the nucleus only in alveolar macrophages that had been exposed to the drug in vivo, suggesting that the lung microenvironment regulated p53 activation. Experiments with a thiol antioxidant (N-acetylcysteine) in vivo and nitric oxide (NO) donors in vitro confirmed that reactive oxygen species were required for p53 activation. A specific role for NO was demonstrated in experiments with inducible nitric oxide synthase (iNOS)(-/)- macrophages, which failed to demonstrate nuclear p53 localization after in vivo bleomycin exposure. Strikingly, rates of bleomycin-induced apoptosis were at least twofold higher in p53(-/)- C57BL/6 mice compared with heterozygous or wild-type littermates. Similarly, levels of apoptosis were also twofold higher in the lungs of iNOS(-/)- mice than were observed in wild-type controls. Consistent with a role for apoptosis in chronic lung injury, levels of bleomycin-induced inflammation were substantially higher in iNOS(-/)- and p53(-/)- mice compared with wild-type controls. Together, our results demonstrate that iNOS and p53 mediate a novel apoptosis-suppressing pathway in the lung.

Show MeSH
Related in: MedlinePlus