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Review
. 2023 Nov 2;21(1):314.
doi: 10.1186/s12964-023-01337-4.

p38 MAPK signaling in chronic obstructive pulmonary disease pathogenesis and inhibitor therapeutics

Ali Ahmadi  1 , Sajjad Ahrari  2 , Jafar Salimian  3 , Zahra Salehi  4 , Mehrdad Karimi  5 , Alireza Emamvirdizadeh  6 , Sadegh Azimzadeh Jamalkandi  7 , Mostafa Ghanei  8
Affiliations
Review

p38 MAPK signaling in chronic obstructive pulmonary disease pathogenesis and inhibitor therapeutics

Ali Ahmadi et al. Cell Commun Signal. .

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar remodeling. Although the abnormalities are primarily prompted by chronic exposure to inhaled irritants, maladjusted and self-reinforcing immune responses are significant contributors to the development and progression of the disease. The p38 isoforms are regarded as pivotal hub proteins that regulate immune and inflammatory responses in both healthy and disease states. As a result, their inhibition has been the subject of numerous recent studies exploring their therapeutic potential in COPD.

Main body: We performed a systematic search based on the PRISMA guidelines to find relevant studies about P38 signaling in COPD patients. We searched the PubMed and Google Scholar databases and used "P38" AND "COPD" Mesh Terms. We applied the following inclusion criteria: (1) human, animal, ex vivo and in vitro studies; (2) original research articles; (3) published in English; and (4) focused on P38 signaling in COPD pathogenesis, progression, or treatment. We screened the titles and abstracts of the retrieved studies and assessed the full texts of the eligible studies for quality and relevance. We extracted the following data from each study: authors, year, country, sample size, study design, cell type, intervention, outcome, and main findings. We classified the studies according to the role of different cells and treatments in P38 signaling in COPD.

Conclusion: While targeting p38 MAPK has demonstrated some therapeutic potential in COPD, its efficacy is limited. Nevertheless, combining p38 MAPK inhibitors with other anti-inflammatory steroids appears to be a promising treatment choice. Clinical trials testing various p38 MAPK inhibitors have produced mixed results, with some showing improvement in lung function and reduction in exacerbations in COPD patients. Despite these mixed results, research on p38 MAPK inhibitors is still a major area of study to develop new and more effective therapies for COPD. As our understanding of COPD evolves, we may gain a better understanding of how to utilize p38 MAPK inhibitors to treat this disease. Video Abstract.

Keywords: COPD; COPD pharmacotherapy; Chronic Obstructive Pulmonary Disease; Systematic review; p38 MAPK inhibitors; p38 MAPK signaling.

Plain language summary

We wanted to determine what studies have been done on how a protein called p38 affects a lung disease called COPD. COPD is a condition that makes it hard to breathe and can cause coughing, wheezing, and chest infections. p38 is a protein that helps cells to respond to stress and inflammation, but it may also play a role in causing or worsening COPD. We searched two main online databases for studies that met our criteria. We looked for studies that involved humans, studies that used animals or cells in the lab, studies that reported new findings, studies that were written in English, and studies that focused on p38 and COPD. We did not include studies that were reviews, summaries, opinions, or letters or studies that were not related to p38 or COPD. We found 361 studies that matched our criteria. We read the titles and summaries of these studies and checked the full texts for quality and relevance. We collected information from each study, such as who did it, when and where it was done, how many people were involved, what type of cells were studied, what treatment was given, what outcome was measured, and what the main results were. We grouped the studies based on the type of cells and type of treatment they studied. We found that different types of cells (such as lung cells, immune cells, and blood cells) and different types of treatment can affect how p38 works in COPD.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flow Diagram Illustrating the Selection Process of Studies for Inclusion in the PRISMA Systematic Review
Fig. 2
Fig. 2
General p38 Signaling Pathways. The figure illustrates the general pathways of p38 signaling. Environmental signals are transmitted through cell receptors (colored orange) to multiple MAPK kinases (MAP3K, colored pink). These MAPKK kinases phosphorylate downstream MAPK kinases (MAPKK, colored green), which subsequently activate the p38 isoforms. In noncanonical pathways, MAPKs can be activated through phosphorylation by ZAP70/SYK or through interaction with TAB1. Once activated, p38 can either remain in the cytoplasm or translocate into the nucleus, leading to the activation of various transcription factors (colored red) and kinase proteins (colored blue)
Fig. 3
Fig. 3
Association of p38 Signaling with COPD Pathogenesis. At the top of the figure, p38 activators and inhibitors are depicted. Downstream of p38 activation, cytokines are highlighted in green, while transcription factors are colored red. Other downstream biomolecules are represented in blue. The figure also highlights cell-specific downstream targets of p38 activation in various immune cell subtypes. However, for other molecules, the target cell types remain unclear
Fig. 4
Fig. 4
Clinical manifestations of the p38α/β signaling pathway. The activation of specific signaling pathways triggers the activation of the p38α/β signaling pathway. This pathway influences various cellular messengers, leading to the development of different phenotypes in diverse cell types
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