title: An Inhaled Inhibitor of Myristoylated Alanine-Rich C Kinase Substrate Reverses LPS-Induced Acute Lung Injury in Mice.
abstract: 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.
authors.affiliation: 1 Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina; and.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yin
authors.affiliation: 1 Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina; and.
authors.forename: Shijing
authors.initials: S
authors.lastname: Fang
authors.forename: Joungjoa
authors.initials: J
authors.lastname: Park
authors.affiliation: 1 Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina; and.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Crews
authors.affiliation: 2 Biomarck Pharmaceuticals, Incorporated, Durham, North Carolina.
authors.forename: Indu
authors.initials: I
authors.lastname: Parikh
authors.affiliation: 1 Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina; and.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Adler
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000188:drug therapy*; D000336:Aerosols / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000378:metabolism; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000336:Aerosols; D016207:Cytokines; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; D010455:Peptides; D000076250:Myristoylated Alanine-Rich C Kinase Substrate
keywords: LPS; acute lung injury; myristoylated alanine-rich C kinase substrate; neutrophils