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mPGES-1 and prostaglandin E2: vital role in inflammation, hypoxic response, and survival
Veronica Siljehav1, Annika Olsson Hofstetter, Per-Johan Jakobsson
1Neonatal Research Unit Q2:07, Department of Women's and Children's Health, Astrid Lindgren Children's Hospital, Stockholm, Sweden.
Background:
Apnea associated with infection and inflammation is a major medical concern in preterm infants. Prostaglandin E(2) (PGE(2)) serves as a critical mediator between infection and apnea. We hypothesize that alteration of the microsomal PGE synthase-1 (mPGES-1) PGE(2) pathway influences respiratory control and response to hypoxia.
Methods:
Nine-d-old wild-type (WT) mice, mPGES-1 heterozygote (mPGES-1(+/-)), and mPGES-1 knockout (mPGES-1(-/-)) mice were used. Respiration was investigated in mice using flow plethysmography after the mice received either interleukin-1β (IL-1β) (10 µg/kg) or saline. Mice were subjected to a period of normoxia, subsequent exposure to hyperoxia, and finally either moderate (5 min) or severe hypoxia (until 1 min after last gasp).
Results:
IL-1β worsened survival in WT mice but not in mice with reduced or no mPGES-1. Reduced expression of mPGES-1 prolonged gasping duration and increased the number of gasps during hypoxia. Response to intracerebroventricular PGE(2) was not dependent on mPGES-1 expression.
Conclusion:
Activation of mPGES-1 is involved in the rapid and vital response to severe hypoxia as well as inflammation. Attenuation of mPGES-1 appears to have no detrimental effects, yet prolongs autoresuscitation efforts and improves survival. Consequently, inhibition of the mPGES-1 pathway may serve as a potential therapeutic target for the treatment of apnea and respiratory disorders.
Insights
Reducing microsomal prostaglandin E synthase-1 (mPGES-1) improved survival and respiratory responses to hypoxia in mice. This suggests mPGES-1 inhibition could treat apnea and respiratory issues.
Area of Science:
- Biomedical Research
- Respiratory Physiology
- Inflammation Studies
Background:
- Apnea in preterm infants is linked to infection and inflammation.
- Prostaglandin E2 (PGE2) mediates infection-induced apnea.
- The role of microsomal prostaglandin E synthase-1 (mPGES-1) in respiratory control is unclear.
Purpose of the Study:
- To investigate the influence of the mPGES-1/PGE2 pathway on respiratory control and hypoxic responses.
- To determine if altering mPGES-1 expression affects apnea and survival.
Main Methods:
- Respiration was measured in wild-type, mPGES-1 heterozygote, and knockout mice using flow plethysmography.
- Mice were exposed to interleukin-1β (IL-1β) or saline, followed by normoxia, hyperoxia, and hypoxia.
- Responses to intracerebroventricular PGE2 were also assessed.
Main Results:
- IL-1β reduced survival in wild-type mice but not in those with reduced or absent mPGES-1.
- Lower mPGES-1 levels prolonged gasping duration and increased gasp frequency during hypoxia.
- PGE2 administration did not depend on mPGES-1 for its effects.
Conclusions:
- mPGES-1 activation is crucial for responses to severe hypoxia and inflammation.
- Reducing mPGES-1 enhances survival and autoresuscitation during hypoxia.
- Inhibiting the mPGES-1 pathway offers a potential therapeutic strategy for apnea and respiratory disorders.
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