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Method Of Action (MOA) in ARDS


BIO-11006 and BIO-10901 both inhibit migration of different cell types, including leukocytes, and specifically, neutrophils. Thus, we looked at the migration of total leukocytes and neutrophils into the lung, measured in the BAL, at 72 hours after LPS instillation. Leukocytes and neutrophil numbers were dramatically increased in the LPS-instilled animals. In addition, neutrophil numbers in the lung were significantly lower in animals treated with peptide and directly proportional to the time post LPS instillation; that is, the earlier treatment began, the fewer neutrophils were present. However, even when treatment was started as long as 36 hours post LPS instillation, neutrophil numbers were significantly lower in the treated animals.

The question relating to the MOA is at what level the peptides are acting to attenuate neutrophil influx into the lung. There are several potential mechanisms that could be relevant:

  1. The inhaled peptides could be having a direct effect on the neutrophils, inhibiting their migration.
  2. The inhaled peptides could be directly decreasing the LPS-induced production/release of pro-inflammatory cytokines by airway epithelial and/or other cell types in the lung, thereby decreasing the chemoattractant signals drawing neutrophils into the lung. Indeed, production of the potent neutrophil chemoattractant cytokine KC (the mouse IL-8 equivalent) was significantly inhibited in the lungs of treated mice at both the protein and mRNA levels.
  3. The inhaled peptides could be directly decreasing the LPS-induced activation of the pro-inflammatory transcription factor, NF-?B, in airway epithelial and other lung cells, thereby decreasing production of KC and other pro-inflammatory cytokines. Indeed, activation of NF-?B was inhibited in the lungs of treated mice.

At this point, given the interrelationships of the above potential mechanisms, it would appear that the inhaled peptides’ MOA involves all of these.