Inducible nitric oxide synthase and heme oxygenase-1 in the lung during lipopolysaccharide tolerance and cross tolerance.

Abstract

OBJECTIVE:

Pretreatment with low-dose lipopolysaccharide protects cells/organs against a subsequent lethal Gram-negative (lipopolysaccharide tolerance) or Gram-positive (cross tolerance) stimulus. We determined whether this occurs in the rat lung. The involvement of inducible nitric oxide synthase and heme oxygenase-1 was evaluated.

DESIGN:

Laboratory study.

SETTING:

University hospital laboratory.

SUBJECTS:

Anesthetized male Wistar rats.

INTERVENTIONS:

To test the hypothesis, rats received saline or lipopolysaccharide (1 mg/kg). At 2, 4, 8, 16, or 24 hrs later, blood samples and lung tissue were taken to determine messenger RNA, protein concentration, and activity of inducible nitric oxide synthase and heme oxygenase-1. In additional experiments, rats were challenged with lipopolysaccharide (1 mg/kg) and subjected to Gram-negative (lipopolysaccharide) or Gram-positive (lipoteichoic acid and peptidoglycan) shock 24 hrs later. These studies were carried out in the presence and absence of inducible nitric oxide synthase or heme oxygenase-1 inhibitors (1400W or tin protoporphyrin IX). Following 6 hrs of shock, lung tissue was taken to determine lung damage and heme oxygenase-1 concentration and activity.

MEASUREMENTS AND MAIN RESULTS:

In the rat lung, lipopolysaccharide (1 mg/kg) induced a significant increase in inducible nitric oxide synthase protein at 8 hrs with a corresponding increase in plasma nitrate/nitrite at 8-16 hrs. Simultaneously, heme oxygenase-1 messenger RNA transcripts were observed at 8-16 hrs, and maximal expression of the protein followed (24 hrs). Pretreatment with low-dose lipopolysaccharide reduced myeloperoxidase activity (neutrophil infiltration) and wet-dry ratio (pulmonary edema) in the lungs of animals subjected to Gram-negative or Gram-positive shock, demonstrating tolerance. Pretreatment with low-dose lipopolysaccharide and the selective inducible nitric oxide synthase inhibitor 1400W reduced heme oxygenase-1 protein expression, and lung protection was abolished. Tin protoporphyrin IX did not affect heme oxygenase-1 expression, but heme oxygenase activity and lung protection were significantly reduced.

CONCLUSIONS:

We propose that nitric oxide (most likely inducible nitric oxide synthase derived) regulates the induction of heme oxygenase-1 in the lung, which in turn plays an important part in pulmonary protection during lipopolysaccharide tolerance and cross tolerance.

• Authors: Alexander Koch, Olaf Boehm, Paula A Zacharowski, Stephan A Loer, Jörg Weimann, Hauke Rensing, Simon J Foster, Rene Schmidt, Reinhard Berkels, Sonja Reingruber, Kai Zacharowski
• Journal: Critical care medicine (Crit Care Med) Vol. 35 Issue 12 Pg. 2775-84 (Dec 2007) ISSN: 0090-3493 [Print] United States
• PMID: 17901834 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipopolysaccharides
• Nitric Oxide Synthase Type II
• Heme Oxygenase-1

Topics

• Animals
• Desensitization, Immunologic
• Gene Expression Regulation (immunology)
• Gram-Negative Bacterial Infections (immunology)
• Gram-Positive Bacterial Infections (immunology)
• Heme Oxygenase-1 (genetics, immunology, metabolism)
• Immune Tolerance (immunology)
• Lipopolysaccharides (immunology)
• Lung (metabolism, pathology)
• Male
• Nitric Oxide Synthase Type II (immunology, metabolism)
• Rats
• Rats, Wistar
• Shock, Septic (immunology, pathology)