p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

ABSTRACT

Introduction: Spontaneous preterm birth (PTB) and preterm premature rupture of the membranes (pPROM) remain as a major clinical and therapeutic problem for intervention and management. Current strategies, based on our knowledge of pathways of preterm labor, have only been effective, in part, due to major gaps in our existing knowledge of risks and risk specific pathways.

Areas covered: Recent literature has identified physiologic aging of fetal tissues as a potential mechanistic feature of normal parturition. This process is affected by telomere dependent and p38 mitogen activated protein kinase (MAPK) induced senescence activation. Pregnancy associated risk factors can cause pathologic activation of this pathway that can cause oxidative stress induced p38 MAPK activation leading to senescence and premature aging of fetal tissues. Premature aging is associated with sterile inflammation capable of triggering preterm labor or preterm premature rupture of membranes. Preterm activation of p38MAPK can be considered as a key contributor to adverse pregnancies.

Expert opinion: This review considers p38MAPK activation as a potential target for therapeutic interventions to prevent adverse pregnancy outcomes mediated by stress factors. In this review, we propose multiple strategies to prevent p38MAPK activation.

KEYWORDS:

• Preterm birth
• premature rupture of membranes
• interventions
• aging
• senescence
• sterile inflammation
• pregnancy and child birth
• oxidative stress

Article highlights

• Human parturition at term is associated with telomere dependent and oxidative stress induced p38MAPK α/β (two dominant isoforms of p38 expressed in fetal tissues) mediated senescence of fetal tissues.

• p38MAPK α/β mediated fetal tissue senescence generates signals (sterile inflammation) that can trigger term parturition.

• Preterm parturition is associated to premature activation of p38MAPK α/β mediated senescence activation and signaling due to excessive oxidative stress and inflammation in response to various risk factors.

• Risk factors such as behavioral (cigarette smoking, alcohol, drug abuse), environmental pollutants, malnutrition, high or low BMI, tissue damage products (in response to oxidative stress due to infection or other risk exposures) can cause preterm p38MAPK activation accelerating premature fetal tissue senescence and untimely signaling of initiation labor (preterm labor). This condition is more dominant in the subset of preterm birth complicated by preterm premature rupture of the membranes (pPROM).

• Inhibition of p38MAPK α/β has reversed oxidative stress induced senescence and sterile inflammation in pregnant animal models and in in vitro fetal membrane tissue/cell culture models.

• Therapeutic interventions to slow down p38MAPK mediated senescence may be beneficial to reduce preterm labor risk in major subset of women with intrauterine oxidative stress due to various risk factors.

• We present intervention strategies and a plan to control the activation and/or activity of the p38MAPK α/β stress response pathway specifically for in vivo treatment of intrauterine tissues.

• The aims of this review are to present protocols that target specific p38α/β activities as a form of specific intervention of PTB and pPROM.

• We discuss the development and use of antedrug and prodrug strategy to apply specific treatment of intrauterine tissues experiencing inflammation-oxidative stress induced p38MAPK α/β linked pathophysiology.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This review was supported by a NIH/NICHD grant [1R03HD08635401] and an Innovative Catalyst Grant from March of Dimes Center of Ohio to R Menon.