FIBREX Medical, Inc.

Objective: Pretreatment with low-dose lipopolysaccharide protects cells/organs against a subsequent lethal Gram-neg. (lipopolysaccharide tolerance) or Gram-pos. (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 laboratorySubjects: Anesthetized male Wistar rats.Interventions: To test the hypothesis, rats received saline or lipopolysaccharide (1 mg/kg).At 2, 4, 8, 16, or 24 h later, blood samples and lung tissue were taken to determine mRNA, protein concentration, and activity of inducible nitric oxide synthase and heme oxygenase-1.In addnl. experiments, rats were challenged with lipopolysaccharide (1 mg/kg) and subjected to Gram-neg. (lipopolysaccharide) or Gram-pos. (lipoteichoic acid and peptidoglycan) shock 24 h 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 h 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 h with a corresponding increase in plasma nitrate/nitrite at 8-16 h.Simultaneously, heme oxygenase-1 mRNA transcripts were observed at 8-16 h, and maximal expression of the protein followed (24 h).Pretreatment with low-dose lipopolysaccharide reduced myeloperoxidase activity (neutrophil infiltration) and wet-dry ratio (pulmonary edema) in the lungs of animals subjected to Gram-neg. or Gram-pos. 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.

A review.FX06 (fibrin derived peptide Bβ15-42) is a promising new drug candidate indicated for the prevention of reperfusion injury in patients undergoing primary percutaneous intervention (PCI) for acute myocardial infarction (AMI).This novel peptide has been shown to prevent myocardial reperfusion injury in a number of acute and chronic animal models for this disease when given as a single bolus injection at the time of reperfusion.FX06 has a novel mechanism of action: it is a competitive inhibitor of the binding of fibrin E1 fragments to vascular endothelial (VE)-cadherin.Through this inhibition, it potently blocks the transmigration of inflammatory leukocytes through the endothelial barrier and prevents the downstream release of tissue-damaging mediators.FX06 has proven safe in acute and subchronic toxicol. studies and recently entered clin. development.