mPGES-1 and prostaglandin E2: vital role in inflammation, hypoxic response, and survival

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-1 beta (IL-1 beta) (10 mu g/kg) or saline. Mice were subjected to a period of normoxia, subsequent exposure to hyperoxia, and finally either moderate (5min) or severe hypoxia (until 1 min after last gasp). RESULTS: IL-1 beta 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.