Safety and efficacy of p38 mitogen-activated protein kinase inhibitors (MAPKIs) in COPD

Yu, Haichuan; Su, Xiaojie; Lei, Ting; Zhang, Lu; Feng, Zhouzhou; Zhang, Chuchu; Zhang, Meng; Wang, Yalei; Chen, Xinlong; Liu, Jian

doi:10.3389/fphar.2022.950035

Cited by 5 publications

(7 citation statements)

References 39 publications

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“…For ethical reasons, we have tested only p38 inhibition in the mouse model, and here, we confirmed that systemic pretreatment with SB203580 preventively attenuated MHV-68 reactivation induced by pulmonary CNP exposure. Thus, p38 might serve as potential therapeutic target in emphysematous CLDs related to ambient particle exposure, and p38 inhibition is already a drug target for chronic inflammatory lung diseases such as COPD. , Even if the results of clinical trials evaluating p38 MAPK inhibitors as drugs for COPD therapy are currently controversial, this could be different for COPD observed in never-smokers where exposure and mechanisms of disease development might differ as well.…”

Section: Discussionmentioning

confidence: 99%

Nanoparticle-Exposure-Triggered Virus Reactivation Induces Lung Emphysema in Mice

Han,

Haefner,

et al. 2023

ACS Nano

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Nanoparticles (NPs) released from engineered materials or combustion processes as well as persistent herpesvirus infection are omnipresent and are associated with chronic lung diseases. Previously, we showed that pulmonary exposure of a single dose of soot-like carbonaceous NPs (CNPs) or fiber-shaped double-walled carbon nanotubes (DWCNTs) induced an increase of lytic virus protein expression in mouse lungs latently infected with murine γ-herpesvirus 68 (MHV-68), with a similar pattern to acute infection suggesting virus reactivation. Here we investigate the effects of a more relevant repeated NP exposure on lung disease development as well as herpesvirus reactivation mechanistically and suggest an avenue for therapeutic prevention. In the MHV-68 mouse model, progressive lung inflammation and emphysema-like injury were detected 1 week after repetitive CNP and DWCNT exposure. NPs reactivated the latent herpesvirus mainly in CD11b+ macrophages in the lungs. In vitro, in persistently MHV-68 infected bone marrow-derived macrophages, ERK1/2, JNK, and p38 MAPK were rapidly activated after CNP and DWCNT exposure, followed by viral gene expression and increased viral titer but without generating a pro-inflammatory signature. Pharmacological inhibition of p38 activation abrogated CNP- but not DWCNT-triggered virus reactivation in vitro, and inhibitor pretreatment of latently infected mice attenuated CNP-exposure-induced pulmonary MHV-68 reactivation. Our findings suggest a crucial contribution of particle-exposure-triggered herpesvirus reactivation for nanomaterial exposure or air pollution related lung emphysema development, and pharmacological p38 inhibition might serve as a protective target to alleviate air pollution related chronic lung disease exacerbations. Because of the required precondition of latent infection described here, the use of single hit models might have severe limitations when assessing the respiratory toxicity of nanoparticle exposure.

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Section: Discussionmentioning

confidence: 99%

Nanoparticle-Exposure-Triggered Virus Reactivation Induces Lung Emphysema in Mice

Han,

Haefner,

et al. 2023

ACS Nano

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“…In the context of COPD, p38 inhibition has been observed to effectively mitigate inflammation and oxidative stress in the pulmonary and muscular tissues of affected individuals, which are closely associated with airflow restriction, respiratory distress, and reduced physical tolerance [55,174]. Moreover, the p38 inhibitors have demonstrated the capability to improve key lung function parameters and alleviate dyspnea in COPD patients, as assessed through measurements such as forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and transition dyspnea index (TDI) [175].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the p38 inhibitors have demonstrated the capability to improve key lung function parameters and alleviate dyspnea in COPD patients, as assessed through measurements such as forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and transition dyspnea index (TDI) [175]. Notably, p38 inhibitors appear to offer superior therapeutic outcomes compared to steroids for specific subsets of COPD patients, given that steroids possess limited antiinflammatory efficacy and are not recommended as standalone treatments for COPD [55,174]. However, it is important to acknowledge that p38 inhibitors may entail undesirable adverse effects, including liver toxicity and cutaneous reactions, which impose restrictions on their clinical usage and raise concerns regarding their safety [16].…”

Section: Discussionmentioning

confidence: 99%

“…A recently published systematic review and metaanalysis evaluated the safety and efficacy of p38 MAPKIs as an alternative to corticosteroids in the treatment of COPD in ten randomized controlled trials (RCTs) involving a total of 1,751 participants [44,55,56,144,146,149,158,160,172,173]. The analysis focused on various outcome measures, including lung function, inflammatory biomarkers, and quality of life [174]. The results indicated that while p38 MAPKIs were found to be safe, they did not demonstrate significant effects compared to placebo in terms of efficacy.…”

Section: Insights From Clinical Trialsmentioning

confidence: 99%

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

Ahmadi,

Ahrari,

Salimian

et al. 2023

Cell Commun Signal

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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.

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“…Oral administration of this class of drugs at safe doses is likely insufficient to induce significant clinical benefit. 60 However, inhaled p38 MAPK inhibitors may lead to a higher local drug concentrations in the lung. An alternative approach could be the development of selective inhibitors of the α-δ subgroups.…”

Section: Inhibition Of Recruitment and Activation Of The Inflammatory...mentioning

confidence: 99%

Novel Anti-Inflammatory Approaches to COPD

Cazzola¹,

Hanania²,

Page³

et al. 2023

COPD

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Airway inflammation, driven by different types of inflammatory cells and mediators, plays a fundamental role in COPD and its progression. Neutrophils, eosinophils, macrophages, and CD4 + and CD8 + T lymphocytes are key players in this process, although the extent of their participation varies according to the patient's endotype. Anti-inflammatory medications may modify the natural history and progression of COPD. However, since airway inflammation in COPD is relatively resistant to corticosteroid therapy, innovative pharmacological anti-inflammatory approaches are required. The heterogeneity of inflammatory cells and mediators in annethe different COPD endo-phenotypes requires the development of specific pharmacologic agents. Indeed, over the past two decades, several mechanisms that influence the influx and/or activity of inflammatory cells in the airways and lung parenchyma have been identified. Several of these molecules have been tested in vitro models and in vivo in laboratory animals, but only a few have been studied in humans. Although early studies have not been encouraging, useful information emerged suggesting that some of these agents may need to be further tested in specific subgroups of patients, hopefully leading to a more personalized approach to treating COPD.

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Safety and efficacy of p38 mitogen-activated protein kinase inhibitors (MAPKIs) in COPD

Cited by 5 publications

References 39 publications

Nanoparticle-Exposure-Triggered Virus Reactivation Induces Lung Emphysema in Mice

Nanoparticle-Exposure-Triggered Virus Reactivation Induces Lung Emphysema in Mice

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

Novel Anti-Inflammatory Approaches to COPD

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