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

Yin, Qi; Fang, Shiaofen; Park, Joungjoa; Crews, Anne L.; Parikh, Indu; Adler, Kenneth B.

doi:10.1165/rcmb.2016-0236rc

Cited by 18 publications

(15 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The marked decrease in nucleated cells in BALf after treatment with PIP-2 suggests that this function of ROS is important for the recovery from lung injury. In that respect, a peptide inhibitor of the myristoylated alanine-rich C kinase substrate (Marcks) protein also protects against lung injury with LPS in mice [44]. Although this latter peptide has not been shown to inhibit NOX2 activation, its effects may be mediated through altered cellular motility that prevents PMN influx into the lung.…”

Section: Discussionmentioning

confidence: 99%

A Peptide Inhibitor of NADPH Oxidase (NOX2) Activation Markedly Decreases Mouse Lung Injury and Mortality Following Administration of Lipopolysaccharide (LPS)

Fisher

Dodia

Chatterjee

et al. 2019

IJMS

View full text Add to dashboard Cite

We have previously derived three related peptides, based on a nine-amino acid sequence in human or rat/mouse surfactant protein A, that inhibit the phospholipase A2 activity of peroxiredoxin 6 (Prdx6) and prevent the activation of lung NADPH oxidase (type 2). The present study evaluated the effect of these Prdx6-inhibitory peptides (PIP) in a mouse (C57Bl/6) model of acute lung injury following lipopolysaccharide (LPS) administration. All three peptides (PIP-1, 2 and 3) similarly inhibited the production of reactive O2 species (ROS) in isolated mouse lungs as detected by the oxidation of Amplex red. PIP-2 inhibited both the increased phospholipase A2 activity of Prdx6 and lung reactive oxygen species (ROS) production following treatment of mice with intratracheal LPS (5 µg/g body wt.). Pre-treatment of mice with PIP-2 prevented LPS-mediated lung injury while treatment with PIP-2 at 12 or 16 h after LPS administration led to reversal of lung injury when evaluated 12 or 8 h later, respectively. With a higher dose of LPS (15 µg/g body wt.), mortality was 100% at 48 h in untreated mice but only 28% in mice that were treated at 12–24 h intervals, with PIP-2 beginning at 12 h after LPS administration. Treatment with PIP-2 also markedly decreased mortality after intraperitoneal LPS (15 µg/g body wt.), used as a model of sepsis. This study shows the dramatic effectiveness of a peptide inhibitor of Prdx6 against lung injury and mouse mortality in LPS models. We propose that the PIP nonapeptides may be a useful modality to prevent or to treat human ALI.

show abstract

Section: Discussionmentioning

confidence: 99%

A Peptide Inhibitor of NADPH Oxidase (NOX2) Activation Markedly Decreases Mouse Lung Injury and Mortality Following Administration of Lipopolysaccharide (LPS)

Fisher

Dodia

Chatterjee

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…Several studies have reported that the application of LPS can induce inflammation in mice (Zhou et al, 2013; Yin et al, 2016). The purpose of this study was to explore the effect of pregnancy ‐related gynaecological diseases on anxiety‐related behaviours in offspring.…”

Section: Introductionmentioning

confidence: 99%

Prenatal maternal vaginal inflammation increases anxiety and alters HPA axis signalling in adult male mice

Wang

Pei²,

Ridong

et al. 2019

Intl J of Devlp Neuroscience

View full text Add to dashboard Cite

Background Maternal infection during pregnancy is known to adversely affect foetal development, but previous studies have rarely investigated the impact of gynaecological diseases during pregnancy on offspring during adulthood. Vaginitis is one of the most prevalent gynaecological diseases during pregnancy. Methods The effect of maternal vaginal inflammation on offspring was simulated by inducing maternal vaginal infection. We performed a transvaginal injection of lipopolysaccharide (LPS) in pregnant mice to induce vaginitis and investigated their offspring by means of behavioural tests and molecular and cellular measurements. Results Behavioural tests revealed that the offspring of mothers transvaginally injected with LPS exhibited sex‐dependent differences. Male offspring showed increased anxiety‐related behaviours, including reduced time exploring the open arm in the elevated plus maze test and light chamber in the light‐dark box test. Serum levels of corticosterone were increased in LPS male offspring, indicating activation of the hypothalamic‐pituitary‐adrenal (HPA) axis. Corticotropin‐releasing hormone (CRH) protein expression and c‐Fos positive cells were increased in the hypothalamic paraventricular nucleus (PVN) in LPS male offspring, which presented with an increased number of microglia. Conclusion This study suggests that prenatal vaginal infection increases anxiety‐like behaviour in male offspring, possibly via activation of the HPA axis.

show abstract

“…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, BAL fluid protein concentrations, leukocyte and neutrophil numbers, KC (keratinocyte chemoattractant; CXCL1, mouse IL-8 equivalent) and TNF-a gene and protein expression, and NF-kB activation were all significantly attenuated by inhaled BIO-11006 at all time points (23). The fact that the treatment was effective as long as 36 hours after administration of LPS to the mice suggests that inhaled MARCKS inhibitors could be an effective treatment for patients who present with already-active ARDS.…”

Section: Ardsmentioning

confidence: 94%

“…Structure MARCKS binds and cross-links actin, bridges calmodulin (CaM) and PKC signaling, and sequesters phosphatidylinositol 4,5-bisphosphate (PIP 2 ) in the plasma membrane (1)(2)(3)(4)(5)(6). Associated with cellular events that require actin, including adhesion, migration and exocytosis (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), it is involved in pulmonary disorders such as chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS) and lung cancer (12,17,(20)(21)(22)(23). In 1982, Wu and colleagues described an "87 kD" PKC substrate protein that is known today as "MARCKS" (6,24).…”

Section: Properties Of Marcks Proteinmentioning

confidence: 99%

“…The solubility of this peptide was greatly enhanced by substituting an acetyl group for the myristic acid moiety. This peptide, called BIO-11006, is resistant to hydrolysis in airway lining fluid and has been shown to be equally as effective as MANS in attenuating mucus secretion, inflammation, and cell motility in several in vitro and in vivo systems (22,23,(97)(98)(99)(100). BIO-11006 was developed as an inhaled aerosol drug by BioMarck Pharmaceuticals and is the basis for several clinical trials in different lung diseases, discussed below.…”

Section: Role In Cellular Functionmentioning

confidence: 99%

See 1 more Smart Citation

MARCKS and Lung Disease

Sheats¹,

Yin

Fang

et al. 2019

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

MARCKS (myristoylated alanine-rich C kinase substrate) is a prominent PKC substrate expressed in all eukaryotic cells. It is known to bind to and cross-link actin filaments, to serve as a bridge between Ca 21 /calmodulin and PKC signaling, and to sequester the signaling molecule phosphatidylinositol 4,5-bisphosphate in the plasma membrane. Since the mid-1980s, this evolutionarily conserved and ubiquitously expressed protein has been associated with regulating cellular events that require dynamic actin reorganization, including cellular adhesion, migration, and exocytosis. More recently, translational studies have implicated MARCKS in the pathophysiology of a number of airway diseases, including chronic obstructive pulmonary disease, asthma, lung cancer, and acute lung injury/acute respiratory distress syndrome. This article summarizes the structure and cellular function of MARCKS (also including MARCKS family proteins and MARCKSL1 [MARCKS-like protein 1]). Evidence for MARCKS's role in several lung diseases is discussed, as are the technological innovations that took MARCKS-targeting strategies from theoretical to therapeutic. Descriptions and updates derived from ongoing clinical trials that are investigating inhalation of a MARCKStargeting peptide as therapy for patients with chronic bronchitis, lung cancer, and ARDS are provided.

show abstract

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

Cited by 18 publications

References 27 publications

A Peptide Inhibitor of NADPH Oxidase (NOX2) Activation Markedly Decreases Mouse Lung Injury and Mortality Following Administration of Lipopolysaccharide (LPS)

A Peptide Inhibitor of NADPH Oxidase (NOX2) Activation Markedly Decreases Mouse Lung Injury and Mortality Following Administration of Lipopolysaccharide (LPS)

Prenatal maternal vaginal inflammation increases anxiety and alters HPA axis signalling in adult male mice

MARCKS and Lung Disease

Contact Info

Product

Resources

About