Abstract
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.
Highlights
Acute lung injury (ALI) is a syndrome manifested by diffuse damage to lung cells resulting in alteration of the alveolar permeability barrier with subsequent lung edema and altered gas exchange [1]
We have recently described the pathway from an initiating signal that activates the phospholipase A2 (PLA2) activity of peroxiredoxin 6 (Prdx6) leading to activation of the crucial Rac protein in polymorphonuclear leukocytes (PMN), alveolar macrophages (AM), and endothelial cells (EC) [23,24,26,27]
We have proposed that the mechanism for the protection afforded by Prdx6-inhibitory peptides (PIP)-2 is its inhibition of the aiPLA2 activity of Prdx6 by allosteric effects resulting from binding of the peptide to Prdx6 [31]
Summary
Acute lung injury (ALI) is a syndrome manifested by diffuse damage to lung cells resulting in alteration of the alveolar permeability barrier with subsequent lung edema and altered gas exchange [1]. ROS can be produced in the lung through several mechanisms, including (a) auto-oxidation reactions, involving the mitochondrial respiratory chain or various other molecules such as quinones and ferrous iron; (b) as a by-product of the enzymatic activity of xanthine oxidase; and (c) through enzymatic activity of NADPH oxidase (NOX) enzymes [7,8,9]. The latter is a widely distributed family of seven enzymes that utilize NADPH to generate either superoxide anion (O2−) or H2O2 as a primary product [10,11]. It is known that ROS generated by NOX enzymes are crucial for the regulation of many important cell functions such as host defense, cellular signaling, cell migration, cell differentiation, and post-translational protein processing [11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
