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 and its functional effects.

Aquaporin-3 Attenuates Oxidative Stress-Induced Nucleus Pulposus Cell Apoptosis Through Regulating the P38 MAPK Pathway

“…Oxidative damage increased activity of the p38 MAPK pathway Mitogen-activated protein kinases (MAPKs) are important in regulating cellular biology [26]. Previous studies have demonstrated that the p38 MAPK pathway can be activated under oxidative damage [27] and inhibition of the p38 MAPK pathway has the potential to protect against disc degeneration [28]. Here, our results confirmed that activity of the p38 MAPK pathway was significantly increased by oxidative damage (Fig.…”

Regulation of p38 mitogen‐activated kinase‐mediated fetal membrane senescence by statins

“…Premature aging in response to OSinducing risk factors can be linked to PTB and pPROM. 22,23 Although there are 4 p38MAPK isoforms, the α and β isoforms are the proteins whose activities are associated with normal physiologic processes as well as major physiologic characteristics of diseases of inflammation and OS that include age-associated diseases. 12,19 Behavioral risk factors, environmental pollutants, and infection are some of the risk factors capable of generating this pathway.…”

Mapping out p38MAPK

“…The fetal membranes are a multilayered and multicellular tissue that includes the amnion and the chorion. 85 Over time in normal pregnancy the fetal membranes undergo senescence associated with increased expression of p38 346, 38 , and express increased p38 with oxidative stress, 24 and in the setting of premature rupture of membranes 6, 71, 86, 87,72 . Membranes express both classical and alternative p38 pathway molecules, but cell type specificity, and the exact up and downstream activators and effectors are not known.…”

“…96 Focus has been on inhibition of the catalytic activity of p38 is through competitive or non-competitive binding of ATP 97 . Many inhibitors of p38 are being considered, including SB203580 (a competitive binder in the ATP pocket or p38), and BIRB 796 97 in diseases related to premature ageing (e.g.…”

“…Focus on how to target drug activity and limit side effects continues. Further, there exists a pipeline to develop ways to modulate molecules down stream of p38 activation 81, 96 in specific cell types 98 order to increase specificity. Relevant clinical trials focusing on reproductive outcome need to be developed.…”