A Drosophila model of cigarette smoke induced COPD identifies Nrf2 signaling as an expedient target for intervention

Prange, R.; Thiedmann, Marcus; Bhandari, Anita; Mishra, Neha; Sinha, Anupam; Häsler, Robert; Rosenstiel, Philip; Uliczka, Karin; Wagner, Christina; Yildirim, Ali Önder; Fink, Christine; Roeder, Thomas

doi:10.18632/aging.101536

Cited by 20 publications

(31 citation statements)

References 67 publications

(70 reference statements)

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“…Chronic obstructive pulmonary disease (COPD) and asthma are the two most common respiratory disorders, and they constitute chronic non-specific lung diseases (CNSLD) [1]. COPD and asthma share many phenotype similarities, such as airflow limitation, breathlessness, dyspnea, coughing, wheezing and chronic inflammation [2,3]. Evidence is mounting suggesting that COPD and asthma are complex multifactorial diseases, involving many environmental and genetic components [4,5].…”

Section: Introductionmentioning

confidence: 99%

Association of RAGE gene multiple variants with the risk for COPD and asthma in northern Han Chinese

Niu

et al. 2019

Aging

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Clinical and experimental data have shown that the receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of respiratory disorders. In this study, we genotyped five widely-evaluated variants in RAGE gene, aiming to assess their association with the risk for chronic obstructive pulmonary disease (COPD) and asthma in northern Han Chinese. Genotypes were determined in 105 COPD patients, 242 asthma patients and 527 controls. In single-locus analysis, there was significant difference in the genotype distributions of rs1800624 between COPD patients and controls ( p =0.022), and the genotype and allele distributions of rs1800625 differed significantly ( p =0.040 and 0.016) between asthma patients and controls. Haplotype analysis revealed that haplotype T-A-G-T (allele order: rs1800625, rs1800624, rs2070600, rs184003) was significantly associated with a reduced COPD risk (OR=0.32, 95% CI: 0.06-0.60), and haplotype T-A-A-G was significantly associated with a reduced asthma risk (OR=0.19, 95% CI: 0.04-0.96). Further haplotype-phenotype analysis showed that high- and low-density lipoprotein cholesterol and blood urea nitrogen were significant mediators for COPD ( p sim =0.041, 0.043 and 0.030, respectively), and total cholesterol was a significant mediator for asthma ( p sim =0.009). Taken together, our findings indicate that RAGE gene is a promising candidate for COPD and asthma, and importantly both disorders are genetically heterogeneous.

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“…For completeness, it should be mentioned here that the abbreviation "NAMs" is often used in toxicology to refer broadly to any non-animal technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment. Examples of NAMs include non-mammalian model systems, (e.g., Caenorhabditis elegans [88][89][90], Drosophila melanogaster [91][92][93], zebrafish [94][95][96] and Dictyostelium [97]) and computational (in silico) approaches [98], which indeed offer opportunities for mimicking human respiratory diseases in a predictive manner. However, the scope of the NAMs considered in our commentary includes only in vitro, non-animal cell models for the testing of OIDs.…”

Section: Limitations Of Current Preclinical Inhalation Testing Stratementioning

confidence: 99%

Preclinical Development of Orally Inhaled Drugs (OIDs)—Are Animal Models Predictive or Shall We Move Towards In Vitro Non-Animal Models?

Movia

Prina-Mello

2020

Animals

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Respiratory diseases constitute a huge burden in our society, and the global respiratory drug market currently grows at an annual rate between 4% and 6%. Inhalation is the preferred administration method for treating respiratory diseases, as it: (i) delivers the drug directly at the site of action, resulting in a rapid onset; (ii) is painless, thus improving patients’ compliance; and (iii) avoids first-pass metabolism reducing systemic side effects. Inhalation occurs through the mouth, with the drug generally exerting its therapeutic action in the lungs. In the most recent years, orally inhaled drugs (OIDs) have found application also in the treatment of systemic diseases. OIDs development, however, currently suffers of an overall attrition rate of around 70%, meaning that seven out of 10 new drug candidates fail to reach the clinic. Our commentary focuses on the reasons behind the poor OIDs translation into clinical products for the treatment of respiratory and systemic diseases, with particular emphasis on the parameters affecting the predictive value of animal preclinical tests. We then review the current advances in overcoming the limitation of animal animal-based studies through the development and adoption of in vitro, cell-based new approach methodologies (NAMs).

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“…Stat92E-GFP was used to monitor the activation of the pathway [21]; the Gal4-UAS system [64] was used to target ectopic expression to the tracheal system. Gal4 drivers used were: btl-Gal4, UAS-GFP on the 3rd chromosome, and btl-Gal4, UAS-GFP on the 2nd chromosome (obtained from the Leptin group, Heidelberg, Germany); upd2-Gal4; upd3-Gal4 [60]; nach-Gal4 [30]. The UAS responders included: UAS-LacZ.nls (BDSC 3956), UAS-…”

Section: Drosophila Strains and Husbandrymentioning

confidence: 99%

Maintaining structural and functional homeostasis of theDrosophilarespiratory epithelia requires stress-modulated JAK/STAT activity

Niu

Fink

Kallsen

et al. 2020

Preprint

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11 12 13 14 15 47 The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling 48 system is of central importance for several critical physiological processes including 49 development, tissue homeostasis, and immune responses [1]. Various cytokines, growth 50 factors, and related signaling compounds signal via this evolutionarily conserved system 51 [2]. The JAK/STAT signaling pathway effectively transduces external signals into desired 52 cellular responses despite having relatively few essential components. Signaling via this 53 pathway is therefore straightforward and allows environmental factors to directly 54 influence transcriptional activity in cells, thereby linking important biological processes 55 with environmental cues [3]. Moreover, JAK/STAT signaling is tightly associated with a 56 great variety of immune responses. JAK/STAT signaling acts downstream of a plethora of 57 cytokines that transmit immune-related information and is, therefore, a central hub in 58 various immunocompetent cells [4-7]. Deregulation of this signaling pathway is directly 59 linked with numerous human diseases, including cancer and inflammatory diseases [5, 8, 60 9]. 61 Lung diseases are often associated with deregulated JAK/STAT signaling. Such 62 deregulation can arise due to mutations and polymorphisms in genes associated with 63 JAK/STAT signaling. In addition, this signaling is activated by stressors, infections, and 64 injuries. This might cause sustained chronic inflammation of the airways and/or alveoli, 65 which is closely associated with the onset and chronification of various lung diseases.66 Niu et al. JAK/STAT signaling in the larval trachea of Drosophila 5 Chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, 67 and lung cancer are causally associated with deregulated JAK/STAT signaling [10]. This 68 signaling is not only of great importance during organ development, but also plays a 69 central role in maintaining tissue and immune homeostasis, especially in response to 70 stressors, infection, and damage [11, 12]. Functional JAK/STAT signaling is required to 71 cope with stressful stimuli such as hyperoxia in the airway epithelium [10]. Deregulation 72 of this signaling in the airways is associated with pathological states. Specifically, 73 chronically reduced JAK/STAT signaling is associated with impaired repair capacities [11], 74 while increased JAK/STAT signaling leads to cell proliferation that can cause cancer [13]. 75 Despite its simple general organization, the JAK/STAT signaling pathway is characterized 76 by multiple redundancies in vertebrates. A multitude of elements function at each level 77 of the JAK/STAT signaling pathway; for example, more than 50 cytokines can activate this 78 pathway [6]. Moreover, deregulation of JAK/STAT signaling in different motile and 79 resident cell types found in the lungs is associated with chronic lung diseases. Therefore, 80 models with a much simpler JAK/STAT pathway and a less complicated cellular 81 compo...

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“…Trachea from control and EGFR CA 3rd instar larvae were manually dissected and the qRT-PCR experiment was performed as described previously (19). rpl32 served as control.…”

Section: Qrt-pcrmentioning

confidence: 99%

An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments

Bossen

Uliczka

Steen

et al. 2019

Molecular Cancer Therapeutics

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Lung cancer is the leading cause of cancer-associated mortality. Mutations in the EGFR gene are among the most important inducers of lung tumor development, but success of personalized therapies is still limited because of toxicity or developing resistances. We expressed constitutively active EGFR (EGFR CA) exclusively in the airway system of Drosophila melanogaster and performed comprehensive phenotyping. Ectopic expression of EGFR CA induced massive hyper-and metaplasia, leading to early death. We used the lethal phenotype as a readout and screened a library of FDA-approved compounds and found that among the 1,000 compounds, only the tyrosine kinase inhibitors (TKI) afatinib, gefitinib, and ibrutinib rescued lethality in a whole-animal screening approach. Furthermore, we screened the library in the presence of a subtherapeutic afatinib dose and identified bazedoxifene as a synergistically acting compound that rescues EGFRinduced lethality. Our findings highlight the potential of Drosophila-based whole-animal screening approaches not only to identify specific EGFR inhibitors but also to discover compounds that act synergistically with known TKIs. Moreover, we showed that targeting the EGFR together with STAT-signaling is a promising strategy for lung tumor treatment.

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“…Thus, there are various mutants as well as transgenic models available, which partly resemble chronic diseases prevalent in humans [17, 18]. In fact, D. melanogaster has been used to study pathologies related to brain function (A beta and tau pathology, Parkinson disease, Huntington disease) [19], respiratory function (asthma, chronic obstructive pulmonary disease (COPD)) [20, 21], motoric function (muscular dystrophy, amylotrophic lateral sclerosis) [22]), renal function (nephtrolithiasis) [23], gut disorders [24], diabetes [25], and heart function (cardiomyopathy) [26] as well as psychiatric disorders (ADHD, alcohol, and other addictions) [27, 28].…”

Section: Introductionmentioning

confidence: 99%

Drosophila melanogaster in nutrition research—the importance of standardizing experimental diets

2019

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The fruit fly Drosophila melanogaster has been increasingly recognized as an important model organism in nutrition research. In order to conduct nutritional studies in fruit flies, special attention should be given to the composition of the experimental diets. Besides complex diets, which are often based on maize, yeast, sucrose, and agar, Drosophila can be also fed chemically defined diets. These so-called holidic diets are standardized in terms of their macro- and micronutrient composition although the quantitative nutrient requirements of flies have yet not been fully established and warrant further investigations. For instance, only few studies address the fatty acid, vitamin, mineral, and trace element requirements of fruit flies. D. melanogaster may be also of interest in the field of nutritional medicine. Diet-induced diabetes and obesity models have been established, and in this context, often, the so-called high-fat and high-sugar diets are fed. However, the composition of these diets is not sufficiently defined and varies between studies. A consensus within the scientific community needs to be reached to standardize the exact composition of experimental complex and holidic diets for D. melanogaster in nutrition research. Since D. melanogaster is an established valuable model system for numerous human diseases, standardized diets are also a prerequisite to conduct diet-disease interaction studies. We suggest that a comprehensive approach, which combines deep phenotyping with disease-related Drosophila models under defined dietary conditions, might lead to the foundation of a so-called fly clinic.

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A Drosophila model of cigarette smoke induced COPD identifies Nrf2 signaling as an expedient target for intervention

Cited by 20 publications

References 67 publications

Association of RAGE gene multiple variants with the risk for COPD and asthma in northern Han Chinese

Preclinical Development of Orally Inhaled Drugs (OIDs)—Are Animal Models Predictive or Shall We Move Towards In Vitro Non-Animal Models?

Maintaining structural and functional homeostasis of theDrosophilarespiratory epithelia requires stress-modulated JAK/STAT activity

An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments

Drosophila melanogaster in nutrition research—the importance of standardizing experimental diets

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