Early inflammatory response to asbestos exposure in rat and hamster lungs: role of inducible nitric oxide synthase

Our plain-English summary of Early inflammatory response to asbestos exposure in rat and hamster lungs: role of inducible nitric oxide synthase, by M. Dörger, A.M. Allmeling, R. Kiefmann, et al (Toxicology and Applied Pharmacology, 2002).

The study

• Authors: M. Dörger, A.M. Allmeling, R. Kiefmann, S. Münzing, K. Messmer, F. Krombach
• Journal: Toxicology and Applied Pharmacology
• Published: 2002;181(2):93-105
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Recent studies have suggested that inducible nitric oxide synthase (iNOS) plays a role in the development of asbestos-related pulmonary disorders. The pulmonary reactions of rats and hamsters upon exposure to asbestos fibers are well known to be disparate. In addition, in vitro experiments have indicated that mononuclear phagocytes from hamsters, in contrast to those from rats, lack the iNOS pathway. Therefore, the purpose of this study was to investigate whether rats and hamsters differ in lung iNOS expression in vivo upon exposure to asbestos fibers and whether differences in iNOS induction are associated with differences in the acute pulmonary inflammatory reaction. Body weight, alveolar-arterial oxygen difference, differential cell count in bronchoalveolar lavage fluid, total protein leakage, lung myeloperoxidase activity and lipidperoxidation, wet/dry ratio, iNOS mRNA and protein expression, and nitrotyrosine staining of lung tissue were determined 1 and 7 days after intratracheal instillation of asbestos fibers in CD rats and Syrian golden hamsters. Exposure of rats to asbestos fibers resulted in enhanced pulmonary iNOS expression and nitrotyrosine staining together with an acute inflammation that was characterized by an influx of neutrophils, enhanced myeloperoxidase activity and lipid peroxidation, damage of the alveolar-capillary membrane, edema formation, and impairment of gas exchange. In comparison, instillation of asbestos fibers in hamsters resulted in a significantly milder inflammatory reaction of the lung with no induction of iNOS in pulmonary cells. The data obtained provide important information to understand the underlying mechanisms of species differences in the pulmonary response upon exposure to asbestos fibers.

In plain English

This was an animal experiment carried out at the University of Munich, Germany. Male CD rats and male Syrian golden hamsters received a single dose of crocidolite asbestos (5 mg/kg body weight) or saline placed directly into the windpipe. Their lungs were examined 1 and 7 days later. The authors studied inducible nitric oxide synthase (iNOS), an enzyme that makes nitric oxide, and signs of lung inflammation. On day 1, asbestos-exposed rats lost weight and showed more iNOS in lung cells. They also had more neutrophils, a type of inflammatory white blood cell: 48.6% of washed-out lung cells, compared with 11.6% in exposed hamsters. Exposed rats also showed protein leakage, lung swelling and poorer oxygen exchange. Exposed hamsters had a milder reaction and no detectable iNOS. By day 7, many of these changes had faded in both species. The authors concluded that the different lung responses of rats and hamsters may be explained, at least in part, by iNOS-derived nitric oxide. They noted that they did not measure how much asbestos reached the lungs. They also noted that the short-lived reaction may mean the dose was too low for long-term effects.

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: single intratracheal instillation of crocidolite asbestos or saline in rats and hamsters, with lungs examined 1 and 7 days afterwards
• Who was studied: Male CD rats (250 to 300 g) and male Syrian golden hamsters (120 to 150 g) bred at the Institute for Surgical Research, Munich, Germany. In each experimental group, eight animals were used for bronchoalveolar lavage and eight for lung tissue sampling. Study dates were not given.
• Exposure: Crocidolite asbestos from the NAIMA Fiber Repository at 5 mg/kg body weight, given once by intratracheal instillation. The fibers had a mean length of 9.9 micrometres (range 1.3 to 30.7) and a mean diameter of 0.3 micrometres (range 0.1 to 1.3). Control animals received saline.
• Main results:
  • Asbestos-exposed rats lost body weight significantly within the first 3 days (for example, 94.5% of baseline on day 3 versus 104.0% in control rats). Asbestos-exposed hamsters did not lose weight.
  • The alveolar-arterial oxygen difference, a measure of gas exchange, increased in asbestos-exposed rats on day 1 and was comparable to controls by day 7. In hamsters it did not differ between control and asbestos groups on either day.
  • On day 1, neutrophils made up 48.6% of lung lavage cells in asbestos-exposed rats versus 11.6% in asbestos-exposed hamsters, a significant difference. On day 7, cell differentials in exposed animals of both species did not differ from saline controls.
  • On day 1, lung myeloperoxidase activity, a marker of neutrophils in lung tissue, was 312.0% of control in asbestos-exposed rats, a significant increase. In asbestos-exposed hamsters it was 149.3% of control, which was not significantly different from control.
  • On day 1, protein in lung lavage fluid, a sign of leaky lung membranes, was 964.3% of control in asbestos-exposed rats, a significant increase. In asbestos-exposed hamsters it was 123.9% of control, not a significant increase.
  • On day 1, lung wet/dry ratio, a measure of fluid in the lung, was 131.6% of control in asbestos-exposed rats. This was significant compared with saline-treated rats and with asbestos-exposed hamsters. Hamster lung water content remained constant.
  • Lipid peroxidation (TBARS), a marker of oxidant burden, rose in both species on day 1: 264.0% of control in rats and 215.4% in hamsters. The increase was significant only in rats.
  • iNOS protein was strongly increased in rat lungs one day after asbestos exposure, in airway epithelium, vessel endothelium and macrophages. It was attenuated by day 7. No iNOS staining was detected in asbestos-exposed hamster lungs on day 1 or day 7.
  • iNOS mRNA increased in rat lungs on day 1 after asbestos exposure. No PCR product was detected in hamster lung tissue on either day with any of the primers used.
  • Nitrotyrosine, an indirect indicator of nitric oxide production, stained strongly in lungs of asbestos-treated rats on day 1 and only weakly in asbestos-treated hamsters. It was not detected in either species on day 7.
  • Under the microscope, asbestos caused hemorrhage, inflammatory cell influx and thickening of alveolar walls on day 1 in both species, more pronounced in rats. By day 7 these signs had almost completely vanished.
• The authors' conclusion: The authors concluded that the disparate lung responses of rats and hamsters to asbestos fibers may be attributable, at least in part, to iNOS-derived nitric oxide. They stated that a study in iNOS-deficient animals was in process to confirm this.
• Limitations the authors state:
  • The authors did not measure how much asbestos was deposited in the lungs. They assumed, based on earlier studies, that rats and hamsters received a comparable dose.
  • The authors noted that the fading of inflammation by day 7 may mean the fibers were rapidly cleared or the dose was too low to induce long-term effects.
  • The authors noted that substances other than peroxynitrite can also form nitrotyrosine, so nitrotyrosine is not specific to iNOS-derived nitric oxide.

Topics

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

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, Inducible Nitric Oxide Synthase (iNOS), Bronchoalveolar Lavage (BAL), Inflammation.

Related studies

• Dual role of inducible nitric oxide synthase in acute asbestos-induced lung injury — 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)
• Simian virus 40 infection down-regulates the expression of nitric oxide synthase in human mesothelial cells — E. Aldieri, S. Orecchia, et al. (2004)
• Iron inhibits the nitric oxide synthesis elicited by asbestos in murine macrophages — E. Aldieri, D. Ghigo, et al. (2001)

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