Olfactory receptors impact pathophysiological processes of lung diseases in bronchial epithelial cells

IF 4.5 3区 生物学 Q2 CELL BIOLOGY European journal of cell biology Pub Date : 2024-03-30 DOI:10.1016/j.ejcb.2024.151408
Daniel Weidinger , Julian Jacobsen , Desiree Alisch , Hendrik Uebner , Natalie Heinen , Lea Greune , Saskia Westhoven , Kaschin Jamal Jameel , Juliane Kronsbein , Stephanie Pfaender , Christian Taube , Sebastian Reuter , Marcus Peters , Hanns Hatt , Jürgen Knobloch
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Abstract

Background

Therapeutic options for steroid-resistant non-type 2 inflammation in obstructive lung diseases are limited. Bronchial epithelial cells are key in the pathogenesis by releasing the central proinflammatory cytokine interleukine-8 (IL-8). Olfactory receptors (ORs) are expressed in various cell types. This study examined the drug target potential of ORs by investigating their impact on associated pathophysiological processes in lung epithelial cells.

Methods

Experiments were performed in the A549 cell line and in primary human bronchial epithelial cells. OR expression was investigated using RT-PCR, Western blot, and immunocytochemical staining. OR-mediated effects were analyzed by measuring 1) intracellular calcium concentration via calcium imaging, 2) cAMP concentration by luminescence-based assays, 3) wound healing by scratch assays, 4) proliferation by MTS-based assays, 5) cellular vitality by Annexin V/PI-based FACS staining, and 6) the secretion of IL-8 in culture supernatants by ELISA.

Results

By screening 100 potential OR agonists, we identified two, Brahmanol and Cinnamaldehyde, that increased intracellular calcium concentrations. The mRNA and proteins of the corresponding receptors OR2AT4 and OR2J3 were detected. Stimulation of OR2J3 with Cinnamaldehyde reduced 1) IL-8 in the absence and presence of bacterial and viral pathogen-associated molecular patterns (PAMPs), 2) proliferation, and 3) wound healing but increased cAMP. In contrast, stimulation of OR2AT4 by Brahmanol increased wound healing but did not affect cAMP and proliferation. Both ORs did not influence cell vitality.

Conclusion

ORs might be promising drug target candidates for lung diseases with non-type 2 inflammation. Their stimulation might reduce inflammation or prevent tissue remodeling by promoting wound healing.

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嗅觉受体影响支气管上皮细胞肺部疾病的病理生理过程
背景阻塞性肺部疾病中类固醇耐药的非 2 型炎症的治疗方案十分有限。支气管上皮细胞释放中枢性促炎细胞因子白细胞介素-8(IL-8),是发病机制的关键。嗅觉受体(ORs)在各种细胞类型中均有表达。本研究通过研究嗅觉受体对肺上皮细胞相关病理生理过程的影响,探讨了嗅觉受体的药物靶点潜力。采用 RT-PCR、Western 印迹和免疫细胞化学染色法检测 OR 的表达。OR 介导的效应通过以下方法进行分析:1)通过钙成像测量细胞内钙浓度;2)通过发光测定法测量 cAMP 浓度;3)通过划痕测定法测量伤口愈合;4)通过 MTS 测定法测量细胞增殖;5)通过基于 Annexin V/PI 的 FACS 染色法测量细胞活力;6)通过 ELISA 法测量培养上清液中 IL-8 的分泌。结果 通过筛选 100 种潜在的 OR 激动剂,我们发现婆罗门醇和肉桂醛这两种激动剂能增加细胞内的钙浓度。我们检测到了相应受体 OR2AT4 和 OR2J3 的 mRNA 和蛋白质。肉桂醛刺激 OR2J3 会降低 1) 在没有和有细菌和病毒病原体相关分子模式(PAMPs)的情况下的 IL-8,2) 增殖和 3) 伤口愈合,但会增加 cAMP。相反,婆罗门醇刺激 OR2AT4 会增加伤口愈合,但不会影响 cAMP 和增殖。结论 ORs 可能是治疗非 2 型炎症的肺部疾病的候选药物。结论 ORs 可能是治疗非 2 型炎症的肺部疾病的候选药物,刺激 ORs 可能会减轻炎症或通过促进伤口愈合防止组织重塑。
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来源期刊
European journal of cell biology
European journal of cell biology 生物-细胞生物学
CiteScore
7.30
自引率
1.50%
发文量
80
审稿时长
38 days
期刊介绍: The European Journal of Cell Biology, a journal of experimental cell investigation, publishes reviews, original articles and short communications on the structure, function and macromolecular organization of cells and cell components. Contributions focusing on cellular dynamics, motility and differentiation, particularly if related to cellular biochemistry, molecular biology, immunology, neurobiology, and developmental biology are encouraged. Manuscripts describing significant technical advances are also welcome. In addition, papers dealing with biomedical issues of general interest to cell biologists will be published. Contributions addressing cell biological problems in prokaryotes and plants are also welcome.
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