An Inhaled Inhibitor of Myristoylated Alanine-Rich C Kinase Substrate Reverses LPS-Induced Acute Lung Injury in Mice

Am J Respir Cell Mol Biol. 2016 Nov;55(5):617-622. doi: 10.1165/rcmb.2016-0236RC.


Intratracheal instillation of bacterial LPS is a well-established model of acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). Because the myristoylated alanine-rich C kinase substrate (MARCKS) protein is involved in neutrophil migration and proinflammatory cytokine production, we examined whether an aerosolized peptide that inhibits MARCKS function could attenuate LPS-induced lung injury in mice. The peptide, BIO-11006, was delivered at 50 μM via inhalation either just before intratracheal instillation of 5 μg of LPS into Balb/C mice, or 4, 12, 24, or 36 hours after LPS instillation. Effects of BIO-11006 were evaluated via analysis of mouse disease-related behavior, lung histology, bronchoalveolar lavage fluid total protein, neutrophil counts and percentages, cytokine (KC [CXCl1, mouse IL-8 equivalent] and TNF-α) expression, and activation of NF-κB in lung tissue. Treatment with aerosolized BIO-11006 at 0, 4, 12, 24, and even 36 hours after LPS instillation reversed the disease process: mouse behavior returned to normal after two treatments 12 hours apart with the inhaled peptide after LPS injury, whereas control LPS-instilled animals treated with PBS only remained moribund. Histological appearance of inflammation, bronchoalveolar lavage fluid protein levels, leukocyte and neutrophil numbers, KC and TNF-α gene and protein expression, and NF-κB activation were all significantly attenuated by inhaled BIO-11006 at all time points. These results implicate MARCKS protein in the pathogenesis of ALI/ARDS and suggest that MARCKS-inhibitory peptide(s), delivered by inhalation, could represent a new and potent therapeutic treatment for ALI/ARDS, even if administered well after the disease process has begun.

Keywords: LPS; acute lung injury; myristoylated alanine-rich C kinase substrate; neutrophils.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Lung Injury / chemically induced*
  • Acute Lung Injury / drug therapy*
  • Aerosols / administration & dosage
  • Aerosols / pharmacology
  • Animals
  • Behavior, Animal
  • Bronchoalveolar Lavage Fluid
  • Cytokines / metabolism
  • Female
  • Inflammation Mediators / metabolism
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Leukocytes / metabolism
  • Lipopolysaccharides
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / metabolism
  • Mice, Inbred BALB C
  • Myristoylated Alanine-Rich C Kinase Substrate
  • NF-kappa B / metabolism
  • Peptides / administration & dosage*
  • Peptides / pharmacology
  • Peptides / therapeutic use*


  • Aerosols
  • Cytokines
  • Inflammation Mediators
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Marcks protein, mouse
  • Membrane Proteins
  • NF-kappa B
  • Peptides
  • Myristoylated Alanine-Rich C Kinase Substrate