Dual role of inducible nitric oxide synthase in acute asbestos-induced lung injury

Our plain-English summary of Dual role of inducible nitric oxide synthase in acute asbestos-induced lung injury, by M. Dörger, A.M. Allmeling, R. Kiefmann, et al (Free Radical Biology & Medicine, 2002).

The study

• Authors: M. Dörger, A.M. Allmeling, R. Kiefmann, A. Schropp, F. Krombach
• Journal: Free Radical Biology & Medicine
• Published: 2002;33(4):491-501
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Reactive oxygen and nitrogen species have been implicated in the pathogenesis of asbestos fibers-associated pulmonary diseases. By comparing the responses of inducible nitric oxide synthase (iNOS) knockout and wild-type mice we investigated the consequences of iNOS expression for the development of the inflammatory response and tissue injury upon intratracheal instillation of asbestos fibers. Exposure to asbestos fibers resulted in an increased iNOS mRNA and protein expression in the lungs from wild-type mice. Moreover, iNOS knockout mice exhibited an exceeded pulmonary expression and production of TNF-alpha as well as a higher influx of neutrophils into the alveolar space than wild-type mice. In contrast, iNOS knockout animals displayed an attenuated oxidant-related tissue injury reflected in a decrease in protein leakage and LDH release into the alveolar space as well as weaker nitrotyrosine staining of lung tissue compared to wild-type mice. Data presented here indicate that iNOS-derived NO exerts a dichotomous role in acute asbestos-induced lung injury in that iNOS deficiency resulted in an exacerbated inflammatory response but improved oxidant-promoted lung tissue damage.

In plain English

This was an animal experiment from the University of Munich. The authors compared mice lacking the gene for inducible nitric oxide synthase (iNOS), an enzyme that makes nitric oxide, with ordinary (wild-type) mice. Mice in the instillation groups received saline or 2 mg/kg body weight of crocidolite asbestos into the windpipe, and their lungs were examined 24 hours later. In wild-type mice, asbestos increased iNOS in the lungs, including in airway lining cells and macrophages. After asbestos, mice lacking iNOS had more of the inflammatory signal TNF-alpha in lung fluid (146.8 versus 64.9 pg/ml in wild-type mice) and higher lung myeloperoxidase activity, an indirect marker of neutrophils (white blood cells) gathering there. They showed fewer signs of tissue damage. Protein leaking into the air spaces was about 50% lower than in wild-type mice. A cell-damage enzyme (LDH) rose significantly only in wild-type mice. Staining for nitrotyrosine, a marker of nitrogen-based oxidants, was weaker. The authors concluded that iNOS-derived nitric oxide plays a dual role in acute asbestos lung injury. They said long-term effects such as fibrosis or lung tumors need further study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment comparing iNOS knockout mice with wild-type mice after a single intratracheal instillation of asbestos or saline, with lungs examined at 24 hours
• Who was studied: C57BL6/Jx129SvEv iNOS-knockout mice and C57BL6/Jx129SvEv wild-type control mice, bred at the Institute for Surgical Research, Munich, Germany. Figures report results from six to eight experiments per group. Table 2 lists 7 mice per saline or asbestos group and 3 untreated mice per genotype.
• Exposure: 2 mg/kg body weight of crocidolite asbestos (NAIMA Fiber Repository) suspended in saline and injected into the trachea. Saline alone served as the control.
• Main results:
  • After asbestos, TNF-alpha in lung lavage fluid was 146.8 pg/ml in knockout mice and 64.9 pg/ml in wild-type mice (control values 44.1 and 32.3 pg/ml). The increase was significantly higher in the knockout mice.
  • Lung myeloperoxidase (MPO) activity rose after asbestos to 1.5 U/g lung tissue in knockout mice and 0.6 U/g in wild-type mice. The authors used MPO as an indirect marker of neutrophil sequestration. The increase was significantly higher in the knockout mice.
  • After asbestos, protein in lavage fluid, a sign of leaky lungs, was about 50% lower in knockout mice than in wild-type mice (364.4 versus 729.8, mean values).
  • LDH activity in lavage fluid rose after asbestos in both groups (wild-type 57.1, knockout 41.0), but the increase over control was significant only in wild-type mice.
  • In wild-type mice, asbestos produced iNOS protein in bronchial and alveolar epithelial cells and in macrophages associated with asbestos fibers. No iNOS staining was seen in knockout mice.
  • Nitrotyrosine staining was widespread in asbestos-treated wild-type lungs and weak in asbestos-treated knockout lungs.
  • On histology, asbestos-treated knockout mice showed more inflammatory cells than wild-type mice, but no alveolar wall thickening. Alveolar septal thickening was seen in wild-type mice.
• The authors' conclusion: The authors concluded that iNOS-derived nitric oxide has a dichotomous role in acute asbestos-induced lung injury: lacking iNOS worsened the inflammatory response but lessened oxidant-related lung tissue damage.
• Limitations the authors state:
  • The authors could not determine the mechanisms of tyrosine nitration in their study.
  • The authors stated that the mechanism by which iNOS-derived nitric oxide may inhibit TNF-alpha production remains unclear.
  • Only acute (24-hour) effects were studied. The authors stated that long-term effects such as fibrosis or lung tumor development need further investigation.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Asbestosis.

Medical terms in this study, explained in our Lexicon: Inducible Nitric Oxide Synthase (iNOS), LDH Release.

Related studies

• Early inflammatory response to asbestos exposure in rat and hamster lungs: role of inducible nitric oxide synthase — M. Dörger, A.M. Allmeling, et al. (2002)
• Expression of inducible nitric oxide synthase in healthy pleura and in malignant mesothelioma — Y. Soini, K. Kahlos, et al. (2000)
• Regulation of nitric oxide synthase induction by iron and glutathione in asbestos-treated human lung epithelial cells — S.H. Park, A.E. Aust (1998)
• Nitric oxide (NO) synthase activity in the lung and NO synthesis in alveolar macrophages of rats increased on exposure to asbestos — H. Iguchi, S. Kojo, et al. (1996)
• Iron inhibits the nitric oxide synthesis elicited by asbestos in murine macrophages — E. Aldieri, D. Ghigo, et al. (2001)
• Simian virus 40 infection down-regulates the expression of nitric oxide synthase in human mesothelial cells — E. Aldieri, S. Orecchia, et al. (2004)

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