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Interactions of P 1507, a new antioxidant agent, with phagocyte functions
1Istituto di Tisiologia e Malattie Respiratoire, Università degli Studi di Pavia, IRCCS Policlinico San Matteo, Italy.
Abstract:
Toxic oxygen free radicals are believed to play a role in the pathogenesis of a number of respiratory diseases. In particular, pulmonary emphysema may occur because of the oxidative impairment of alpha 1-proteinase inhibitor (alpha 1-PI). We report in vitro data on a new thiol agent, P 1507 [N-5-(thioxo-L-prolyl)-L-cysteine], obtained in a series of experiments designed in view of its therapeutic potential in these clinical conditions. We found that P 1507 at the concentration of 5 x 10(-6) M was able to almost fully abolish the PMA-triggered PMN-induced oxidative impairment of alpha 1-PI. Protection may be due to the radical scavenger ability of P 1507, that markedly reduced superoxide anion production from PMNs. We also found that P 1507 did not significantly impair other defence mechanisms of PMNs (i.e. phagocytosis, chemotaxis and bactericidal activity). The release of cytokines (TNF-alpha, IL-6 and IL-8) from monocytes was not altered in the presence of P 1507. We conclude that the compound P 1507 may be considered for treatment of clinical conditions characterized by overload of oxidants, on the basis of its ability in preventing the oxidative damage of alpha 1-PI and of a lack of unwanted inhibitory effects towards defence mechanisms of phagocytes.
Insights
A new compound, P 1507, protects alpha 1-proteinase inhibitor (alpha 1-PI) from oxidative damage in respiratory diseases. This radical scavenger reduces harmful superoxide production without impairing immune cell functions.
Area of Science:
- Biochemistry
- Pharmacology
- Respiratory Medicine
Background:
- Toxic oxygen free radicals contribute to respiratory disease pathogenesis.
- Oxidative impairment of alpha 1-proteinase inhibitor (alpha 1-PI) is implicated in pulmonary emphysema.
Purpose of the Study:
- To evaluate the therapeutic potential of a new thiol agent, P 1507 [N-5-(thioxo-L-prolyl)-L-cysteine].
- To investigate P 1507's ability to prevent oxidative damage to alpha 1-PI.
Main Methods:
- In vitro experiments assessing P 1507's effect on PMA-triggered PMN-induced oxidative impairment of alpha 1-PI.
- Measurement of superoxide anion production, phagocytosis, chemotaxis, and bactericidal activity of neutrophils (PMNs).
- Analysis of cytokine release (TNF-alpha, IL-6, IL-8) from monocytes in the presence of P 1507.
Main Results:
- P 1507 (5 x 10(-6) M) nearly abolished PMA-triggered PMN-induced oxidative impairment of alpha 1-PI.
- P 1507 significantly reduced superoxide anion production from PMNs, indicating radical scavenging ability.
- P 1507 did not impair PMN defense mechanisms (phagocytosis, chemotaxis, bactericidal activity) or alter monocyte cytokine release.
Conclusions:
- P 1507 demonstrates potential for treating conditions with oxidant overload.
- Its efficacy in preventing alpha 1-PI oxidative damage and lack of adverse effects on phagocyte defense mechanisms support its consideration for clinical use.