p38 MAPK inhibitors, IKK2 inhibitors, and TNFα inhibitors in COPD

Banerjee, Audreesh; Koziol‐White, Cynthia; Panettieri, Reynold A.

doi:10.1016/j.coph.2012.01.016

Cited by 54 publications

(29 citation statements)

References 48 publications

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“…32, 33 In the pathogenic processes of COPD, p38 MAPK signaling has been found to have roles in the activation of inflammation cascade and infiltration of immunocytes in vivo and in vitro . 34 One clinical trial demonstrated a better clinical efficacy in COPD patients receiving p38 MAPK inhibitor therapy.…”

Section: Discussionmentioning

confidence: 99%

Elastase induced lung epithelial cell apoptosis and emphysema through placenta growth factor

et al. 2013

Cell Death Dis

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Chronic pulmonary obstructive disease (COPD) is the fourth leading cause of death worldwide, however, the pathogenic factors and mechanisms are not fully understood. Pulmonary emphysema is one of the major components of COPD and is thought to result from oxidative stress, chronic inflammation, protease–antiprotease imbalance and lung epithelial (LE) cell apoptosis. In our previous studies, COPD patients were noted to have higher levels of placenta growth factor (PlGF) in serum and bronchoalveolar lavage fluid than controls. In addition, transgenic mice overexpressing PlGF developed pulmonary emphysema and exposure to PlGF in LE cells induced apoptosis. Furthermore, intratracheal instillation of porcine pancreatic elastase (PPE) on to PlGF wild type mice induced emphysema, but not in PlGF knockout mice. Therefore, we hypothesized that PPE generates pulmonary emphysema through the upregulation of PlGF expression in LE cells. The elevation of PlGF then leads to LE cell apoptosis. In the present study, we investigated whether PPE induces PlGF expression, whether PlGF induces apoptosis and whether the downstream mechanisms of PlGF are related to LE cell apoptosis. We found that PPE increased PlGF secretion and expression both in vivo and in vitro. Moreover, PlGF-induced LE cell apoptosis and PPE-induced emphysema in the mice were mediated by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways. Given these findings, we suggest that the increase in PlGF and PlGF-induced JNK and p38 MAPK pathways contribute to PPE-induced LE cell apoptosis and emphysema. Regulatory control of PlGF and agents against its downstream signals may be potential therapeutic targets for COPD.

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Section: Discussionmentioning

confidence: 99%

Elastase induced lung epithelial cell apoptosis and emphysema through placenta growth factor

et al. 2013

Cell Death Dis

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“…p38 MAPK inhibitors therefore seem a promising new line of treatment. Currently, several clinical trials explore the feasibility of this approach [82].…”

Section: P38 Mapkmentioning

confidence: 99%

Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease

Meijer

Rijkers

Overveld

2013

Expert Review of Clinical Immunology

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Chronic obstructive pulmonary disease (COPD) is characterized by a decreased airflow due to airway narrowing that, once it occurs, is not fully reversible. The disease usually is progressive and associated with an enhanced inflammatory response in the lungs after exposure to noxious particles or gases. After removal of the noxious particles, the inflammation can continue in a self-sustaining manner. It has been established that improper activation of neutrophils lies at the core of the pathology. This paper provides an overview of the mechanisms by which neutrophils can induce the pulmonary damage of COPD. As the pathogenesis of COPD is slowly being unraveled, new points of intervention are discovered, some of which with promising results.

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“…Indeed, there is ongoing clinical development of MAPK14 inhibitors to block inflammation in COPD and asthma (61,62). In either case, the present identification and validation of the CLCA1 to MAPK13 signaling pathway to excess mucus production offers an opportunity to better define the regulation of a major disease end point and to respond to the unmet need for an anti-mucus therapeutic for inflammatory airway disease.…”

Section: Figurementioning

confidence: 99%

IL-13–induced airway mucus production is attenuated by MAPK13 inhibition

Alevy

Patel²,

Romero³

et al. 2012

J. Clin. Invest.

174

262

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Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13-driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases.

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p38 MAPK inhibitors, IKK2 inhibitors, and TNFα inhibitors in COPD

Cited by 54 publications

References 48 publications

Elastase induced lung epithelial cell apoptosis and emphysema through placenta growth factor

Elastase induced lung epithelial cell apoptosis and emphysema through placenta growth factor

Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease

IL-13–induced airway mucus production is attenuated by MAPK13 inhibition

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