Faculty Opinions recommendation of Interaction of surfactant protein A with peroxiredoxin 6 regulates phospholipase A2 activity.

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.

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Inhibition of Trimeresurus flavoviridis phospholipase A2 by lung surfactant protein A (SP-A)

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism ◽

10.1016/0005-2760(94)90148-1 ◽

1994 ◽

Vol 1211 (3) ◽

pp. 256-262 ◽

Cited By ~ 21

Author(s):

Aron B. Fisher ◽

Chandra Dodia ◽

Avinash Chander ◽

Michael F. Beers ◽

Sandra R. Bates

Keyword(s):

Phospholipase A2 ◽

Lung Surfactant ◽

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A ◽

Trimeresurus Flavoviridis ◽

Lung Surfactant Protein

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Inhibition of lung calcium-independent phospholipase A2 by surfactant protein A

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1994.267.3.l335 ◽

1994 ◽

Vol 267 (3) ◽

pp. L335-L341 ◽

Cited By ~ 14

Author(s):

A. B. Fisher ◽

C. Dodia ◽

A. Chander

Keyword(s):

Phospholipase A2 ◽

Chemical Reduction ◽

Lung Surfactant ◽

Protein A ◽

Lamellar Body ◽

Surfactant Protein ◽

Surfactant Protein A ◽

Lamellar Bodies ◽

Pla2 Activity ◽

Body Protein

The effect of lung surfactant protein A (SP-A) on lung phospholipase A2 (PLA2) activity was investigated. SP-A was purified from bovine surfactant obtained by lung lavage. PLA2 was assayed using radiolabeled 1,2-dipalmitoyl phosphatidylcholine (DPPC) in surfactant-like unilamellar liposomes with Ca(2+)-free acidic (pH 4) or 10 mM Ca2+, alkaline (pH 8.5) buffer. SP-A significantly inhibited Ca(2+)-independent acidic PLA2 of rat lung homogenate or isolated lamellar bodies but had no effect on the Ca(2+)-dependent alkaline enzyme. Lamellar body PLA2 was inhibited by 50% with 0.25 micrograms SP-A/microgram lamellar body protein. Similar inhibition by SP-A was observed when 1-palmitoyl,2-oleoyl PC (POPC) was the substrate. Binding assay showed binding of 125I-labeled SP-A to DPPC but not to POPC, indicating that removal of substrate was not the mechanism for inhibition of the enzyme by SP-A. Chemical reduction or alkylation of SP-A abolished its inhibitory effect on PLA2 activity. Inactivation of endogenous SP-A in isolated lamellar bodies or surfactant increased Ca(2+)-independent PLA2 activity in these fractions. The presence of SP-A in liposomes stimulated the uptake of DPPC by isolated granular pneumocytes in primary culture but significantly inhibited its degradation. These results indicate that the Ca(2+)-independent acidic PLA2 has a role in the metabolism of internalized surfactant phospholipid and that SP-A can modulate the activity of this enzyme.

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