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

Abstract

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.

Il-1β and prostaglandin E2attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice

“…4). That PGE 2 regulates the breathing response to hypoxia is in line with previous data (23,25,43). That PGE 2 regulates the breathing response to hypercapnia via brain stem EP3R is however a new and unexpected finding (Fig.…”

“…The present study thus further underlines that a rapid release of PGE 2 , and hypoxic activation of mPGES-1, is part of the immediate response to severe hypoxia (3,23,25,43). In addition we demonstrate that PGE 2 , via the EP3R, decreases the frequency as well as the duration of gasping efforts.…”

“…In addition to an inflammatory stimulus, hypoxia itself induces PGE 2 synthesis (31) that depresses respiration (43) and might lead to deleterious brain damage (32). During perinatal hypoxia PGE 2 metabolite levels in cerebrospinal fluid are increased and directly correlate with the severity of perinatal asphyxia in human neonates (3).…”

Microglia modulate respiratory rhythm generation and autoresuscitation

“…Although the mechanisms linking these pathological conditions have not been revealed (Huxtable et al, ), it is likely that proinflammatory mediators could affect the generation and control of breathing (Herlenius, ; Huxtable et al, ). For instance, peripheral application of proinflammatory mediators can modulate respiratory centers (Ericsson et al, ; Herlenius, ) and reduce breathing in animals (Frøen et al, ; Guerra et al, ; Hofstetter and Herlenius, ; Hofstetter et al, ; Hutchinson et al, ; Kitterman et al, ; Olsson et al, ; Siljehav et al, ; Stoltenberg et al, ; Tai and Adamson, ) and in humans (Hoch and Bernhard, ; Preas et al, ). Peripheral infection and inflammation can induce central neuroinflammation (Elmore et al, ; Henry et al, ; Liu et al, ), which is produced by microglia (Elmore et al, ; Henry et al, ; Liu et al, ).…”

“…These findings, along with the observation that microglia can produce all the proinflammatory mediators that modulate respiratory rhythm generation (Elmore et al, ; Henry et al, ; Kaur et al, ; Lai and Todd, ; Liu et al, ), suggest that microglia can modulate breathing generation (Huxtable et al, ). This possibility is further supported by the fact that central application of proinflammatory mediators, such as prostaglandin E2 (PGE2) and interleukin‐1β, can modulate respiratory rhythm generation in vivo (Koch et al, ; Olsson et al, ; Siljehav et al, ; Stoltenberg et al, ) and in vitro (Koch et al, ; Olsson et al, ). Since these proinflammatory mediators can be released into the CNS by microglia (Allen et al, ; Elmore et al, ; Henry et al, ; Kaur et al, ; Lai and Todd, ; Liu et al, ; Shohami and Gross, ), changes in the activity of microglia could release these mediators and modulate respiratory rhythm generation (Huxtable et al, ).…”