Unfolded protein response suppression potentiates LPS-induced barrier dysfunction and inflammation in bovine pulmonary artery endothelial cells.

IF 3.6 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Tissue Barriers Pub Date : 2024-04-02 Epub Date: 2023-07-12 DOI:10.1080/21688370.2023.2232245

Nektarios Barabutis, Mohammad S Akhter

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Abstract

The development of novel strategies to counteract diseases related to barrier dysfunction is a priority, since sepsis and acute respiratory distress syndrome are still associated with high mortality rates. In the present study, we focus on the effects of the unfolded protein response suppressor (UPR) 4-Phenylbutyrate (4-PBA) in Lipopolysaccharides (LPS)-induced endothelial injury, to investigate the effects of that compound in the corresponding damage. 4-PBA suppressed binding immunoglobulin protein (BiP) - a UPR activation marker - and potentiated LPS - induced signal transducer and activator of transcription 3 (STAT3) and extracellular signal‑regulated protein kinase (ERK) 1/2 activation. In addition to those effects, 4-PBA enhanced paracellular hyperpermeability in inflamed bovine pulmonary endothelial cells, and did not affect cell viability in moderate concentrations. Our observations suggest that UPR suppression due to 4-PBA augments LPS-induced endothelial injury, as well as the corresponding barrier disruption.

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抑制折叠蛋白反应可增强 LPS 诱导的牛肺动脉内皮细胞屏障功能障碍和炎症。

由于败血症和急性呼吸窘迫综合征的死亡率仍然很高，因此开发新的策略来应对与屏障功能障碍有关的疾病是当务之急。在本研究中，我们重点研究了未折叠蛋白反应抑制剂（UPR）4-苯丁酸（4-PBA）在脂多糖（LPS）诱导的内皮损伤中的作用，以探究该化合物在相应损伤中的效果。4-PBA抑制了结合免疫球蛋白（BiP）--一种UPR激活标记物--并增强了LPS诱导的信号转导和激活转录3（STAT3）和细胞外信号调节蛋白激酶（ERK）1/2的激活。除了这些作用外，4-PBA 还能增强发炎的牛肺内皮细胞的细胞旁高渗透性，而且在中等浓度下不会影响细胞的存活率。我们的观察结果表明，4-PBA 对 UPR 的抑制增强了 LPS 诱导的内皮损伤以及相应的屏障破坏。

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来源期刊

Tissue Barriers MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

6.60

自引率

6.50%

发文量

期刊介绍： Tissue Barriers is the first international interdisciplinary journal that focuses on the architecture, biological roles and regulation of tissue barriers and intercellular junctions. We publish high quality peer-reviewed articles that cover a wide range of topics including structure and functions of the diverse and complex tissue barriers that occur across tissue and cell types, including the molecular composition and dynamics of polarized cell junctions and cell-cell interactions during normal homeostasis, injury and disease state. Tissue barrier formation in regenerative medicine and restoration of tissue and organ function is also of interest. Tissue Barriers publishes several categories of articles including: Original Research Papers, Short Communications, Technical Papers, Reviews, Perspectives and Commentaries, Hypothesis and Meeting Reports. Reviews and Perspectives/Commentaries will typically be invited. We also anticipate to publish special issues that are devoted to rapidly developing or controversial areas of research. Suggestions for topics are welcome. Tissue Barriers objectives: Promote interdisciplinary awareness and collaboration between researchers working with epithelial, epidermal and endothelial barriers and to build a broad and cohesive worldwide community of scientists interesting in this exciting field. Comprehend the enormous complexity of tissue barriers and map cross-talks and interactions between their different cellular and non-cellular components. Highlight the roles of tissue barrier dysfunctions in human diseases. Promote understanding and strategies for restoration of tissue barrier formation and function in regenerative medicine. Accelerate a search for pharmacological enhancers of tissue barriers as potential therapeutic agents. Understand and optimize drug delivery across epithelial and endothelial barriers.