Anti-inflammatory effects of LASSBio-998, a new drug candidate designed to be a p38 MAPK inhibitor, in an experimental model of acute lung inflammation

Lima, Aline C. Brando; Machado, Alexandre Légora; Simon, P.; Cavalcante, Moisés Marinho; Rezende, Daniele C.; Silva, Gilberto M. Sperandio da; Nascimento, Paulo Gustavo Barboni Dantas; Quintas, Luis Eduardo M.; Cunha, Fernando Q.; Barreiro, Eliezer J.; Lima, Lı́dia Moreira; Koatz, Vera Lúcia Gonçalves

doi:10.1016/s1734-1140(11)70619-3

Cited by 14 publications

(6 citation statements)

References 47 publications

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“…Many RBPs are substrates of the p38 MAPK pathway, implying these proteins are part of signaling pathways responding to proinflammatory stimuli [112,113]. A strong link has been established between the p38 pathway and inflammation, including known roles in rheumatoid arthritis, Alzheimer’s disease, inflammatory bowel disease, as well as endotoxin-induced shock, collagen-induced arthritis, and acute lung inflammation [114–118]. In addition, inflammatory cytokines such as TNFα and IL-1 as well as LPS and environmental stresses are known catalysts of initiating p38 signaling.…”

Section: P38 Regulation Of Rbps: a Counterregulatory Mechanism?mentioning

confidence: 99%

Inflammation-regulated mRNA stability and the progression of vascular inflammatory diseases

Herman

Autieri

2017

Clinical Science

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Cardiovascular disease remains a major medical and socioeconomic burden in developed and developing societies, and will increase with an aging and increasingly sedentary society. Vascular disease and atherosclerotic vascular syndromes are essentially inflammatory disorders, and transcriptional and post-transcriptional processes play essential roles in the ability of resident vascular and inflammatory cells to adapt to environmental stimuli. The regulation of mRNA translocation, stability, and translation are key processes of post-transcriptional regulation that permit these cells to rapidly respond to inflammatory stimuli. For the most part, these processes are controlled by elements in the 3'-UTR of labile, proinflammatory transcripts. Since proinflammatory transcripts almost exclusively contain AU-rich elements (AREs), this represents a tightly regulated and specific mechanism for initiation and maintenance of the proinflammatory phenotype. RNA-binding proteins (RBPs) recognize cis elements in 3'-UTR, and regulate each of these processes, but there is little literature exploring the concept that RBPs themselves can be directly regulated by inflammatory stimuli. Conceptually, inflammation-responsive RBPs represent an attractive target of rational therapies to combat vascular inflammatory syndromes. Herein we briefly describe the cellular and molecular etiology of atherosclerosis, and summarize our current understanding of RBPs and their specific roles in regulation of inflammatory mRNA stability. We also detail RBPs as targets of current anti-inflammatory modalities and how this may translate into better treatment for vascular inflammatory diseases.

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Section: P38 Regulation Of Rbps: a Counterregulatory Mechanism?mentioning

confidence: 99%

Inflammation-regulated mRNA stability and the progression of vascular inflammatory diseases

Herman

Autieri

2017

Clinical Science

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“…Inhibition of p38 MAPK using SD‐282 reduces inflammation in a model of tobacco smoke‐induced airway inflammation with decreased expression of cyclooxygenase‐2 (COX‐2) and IL‐6 mRNAs . Studies using pharmacological inhibitors have also implicated p38 MAPK in mouse models of COPD, asthma and acute lung inflammation , suggesting that p38 MAPK inhibition could have therapeutic effects in lung inflammatory diseases.…”

Section: Chronic Obstructive Pulmonary Disease (Copd)mentioning

confidence: 99%

Roles of p38α mitogen‐activated protein kinase in mouse models of inflammatory diseases and cancer

2015

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The p38α mitogen‐activated protein kinase pathway not only regulates the production of inflammatory mediators, but also controls processes related to tissue homeostasis, such as cell proliferation, differentiation and survival, which are often disrupted during malignant transformation. The versatility of this signaling pathway allows for the regulation of many specific functions depending on the cell type and context. Here, we discuss mouse models that have been used to identify in vivo functions of p38α signaling in the pathogenesis of inflammatory diseases and cancer. Experiments using genetically modified mice and pharmacological inhibitors support that targeting the p38α pathway could be therapeutically useful for some inflammatory diseases and tumor types.

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“…Inhalation of LPS has previously been used to induce neutrophilic airway inflammation in humans [ 27 ], laboratory animals [ 28 ], and horses [ 22 , 29 ]. Several studies have shown that inhalation of LPS led to increased neutrophil counts and increased neutrophil ratios in BALF six hours after the challenge in healthy horses [ 22 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of inhaled hydrosoluble curcumin on inflammatory markers in broncho-alveolar lavage fluid of horses with LPS-induced lung neutrophilia

Sandersen

Bienzle

Cerri

et al. 2015

Multidiscip Respir Med

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BackgroundHorses commonly suffer from chronic respiratory disease and are also used in large animal models of spontaneous or induced airway inflammation. The anti-inflammatory properties of curcumin are largely described but its low bioavailability precludes its clinical use. NDS27, a lysin salt of curcumin incorporated in beta-cyclodextrine, has high bioavailability and can be administered by inhalation. The aim of this study was to investigate the effects of inhaled NDS27 on inflammatory cytokines and proteins in the broncho-alveolar lavage fluid using a model of neutrophilic airway inflammation.MethodsAirway neutrophilia was induced in eight horses by inhalation of lipopolysaccharides (LPS). Horses were treated with either inhalation of NDS27 or with placebo in a randomized cross-over design. Broncho-alveolar lavages were performed 6 hours after stimulation with LPS. Percentage of neutrophils, concentrations of IL-1β, TNF-α, IL-6, Club cell secretory protein, myeloperoxidase (MPO) and elastase (ELT) concentrations were determined.ResultsLPS stimulation induced significant increases in neutrophil counts and concentrations of IL-6 (70.2 ± 66.0 pg/ml), TNF-α (43.9 ± 31.2 pg/ml), MPO (580.9 ± 327.0 ng/ml) and ELT (27.6 ± 16.7 ng/ml). Treatment with NDS27 significantly prevented the increase in active and total MPO (216.4 ± 118.1 ng/ml) and ELT (5.9 ± 3.2 ng/ml) while there was a trend towards reduced IL-6 concentration.ConclusionsResults show that, although not reducing neutrophil recruitment, NDS27 largely abolishes LPS-induced neutrophil degranulation. Reduced levels of ELT and MPO, as well as reduced MPO activity may have beneficial effects via a reduced production of reactive oxygen species implicated in chronic inflammation and airway remodeling.

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Anti-inflammatory effects of LASSBio-998, a new drug candidate designed to be a p38 MAPK inhibitor, in an experimental model of acute lung inflammation

Cited by 14 publications

References 47 publications

Inflammation-regulated mRNA stability and the progression of vascular inflammatory diseases

Inflammation-regulated mRNA stability and the progression of vascular inflammatory diseases

Roles of p38α mitogen‐activated protein kinase in mouse models of inflammatory diseases and cancer

Effect of inhaled hydrosoluble curcumin on inflammatory markers in broncho-alveolar lavage fluid of horses with LPS-induced lung neutrophilia

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