2016 journal article
An Inhaled Inhibitor of Myristoylated Alanine-Rich C Kinase Substrate Reverses LPS-Induced Acute Lung Injury in Mice
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 55(5), 617–622.
author keywords: myristoylated alanine-rich C kinase substrate; acute lung injury; LPS; neutrophils
MeSH headings : 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
TL;DR:
Results implicate MARCKS protein in the pathogenesis of ALI/ARDS and suggest that MARC KS-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.
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open access via europepmc.org (repository)
UN Sustainable Development Goal Categories
3. Good Health and Well-being
(Web of Science)
Source: Web Of Science
Added: August 6, 2018
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.