Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

Abstract

Inflammation and apoptosis are crucial mechanisms for the development of the acute respiratory distress syndrome (ARDS). Currently, there is no specific pharmacological therapy for ARDS. We have evaluated the ability of a new family of 1,2,3,5-tetrasubstituted pyrrol compounds for attenuating lipopolysaccharide (LPS)-induced inflammation and apoptosis in an in vitro LPS-induced airway epithelial cell injury model based on the first steps of the development of sepsis-induced ARDS. Human alveolar A549 and human bronchial BEAS-2B cells were exposed to LPS, either alone or in combination with the pyrrol derivatives. Rhein and emodin, two representative compounds with proven activity against the effects of LPS, were used as reference compounds. The pyrrol compound that was termed DTA0118 had the strongest inhibitory activity and was selected as the lead compound to further explore its properties. Exposure to LPS caused an intense inflammatory response and apoptosis in both A549 and BEAS-2B cells. DTA0118 treatment downregulated Toll-like receptor-4 expression and upregulated nuclear factor-κB inhibitor-α expression in cells exposed to LPS. These anti-inflammatory effects were accompanied by a significantly lower secretion of interleukin-6 (IL-6), IL-8, and IL-1β. The observed antiapoptotic effect of DTA0118 was associated with the upregulation of antiapoptotic Bcl-2 and downregulation of proapoptotic Bax and active caspase-3 protein levels. Our findings demonstrate the potent anti-inflammatory and antiapoptotic properties of the pyrrol DTA0118 compound and suggest that it could be considered as a potential drug therapy for the acute phase of sepsis and septic ARDS. Further investigations are needed to examine and validate these mechanisms and effects in a clinically relevant animal model of sepsis and sepsis-induced ARDS.

Development of a physiomimetic model of acute respiratory distress syndrome by using ECM hydrogels and organ-on-a-chip devices

“…Results on the inflammatory response of the developed model to a classic inflammatory hit (i.e., LPS) modeling ARDS were in line with what has been observed in previous in vitro and in vivo studies (Huh et al, 2018;Voiriot et al, 2017;Li et al, 2020;Cabrera-Benítez et al, 2016;Peñuelas et al, 2013). As expected, the inflammatory response observed in the advanced model was attenuated, indicating that the presence of LMSCs and the incorporation of different biophysical stimuli play a protective role in response to an endotoxin hit.…”

“…Therefore, there is an urgent need to develop models with higher physiological relevance to understand the inflammatory processes related to ARDS, the impact of cell therapy ( Nonaka et al, 2020 ), and the use of anti-inflammatory drugs ( Trivedi, Verma, and Kumar 2020 ). Conventional ARDS in vitro models mainly involve applying an inflammatory hit (usually by a bacteriotoxin) to a monolayer of pulmonary epithelial or endothelial cells ( Cabrera-Benítez et al, 2016 ). These conventional models do not fully mimic the complex three-dimensional microarchitecture or the extracellular matrix ( Burgess et al, 2016 ) (ECM) stiffness experienced by cells in vivo.…”

Recent advances in endotoxin tolerance

“…43,45 Studies have shown that endotoxin could significantly induce cell apoptosis in cells and animal models. [46][47][48] Endotoxin induces cell apoptosis mainly by stimulating the vascular cells to induce noncalcium-dependent inducible nitric oxide synthase (iNOS) for production of large amounts of nitric oxide (NO) to activate monocytes, macrophages, and neutrophils for release of cytokines such as TNF-α and further to promote the expression of apoptosis-related receptors, such as Fas, TLR-2, CD14, etc. 49 Another study showed that endotoxin could increase the activities of caspases-1 and -3, induced the cleavage of focal adhesion kinase (FAK), and increase the expressions of the proapoptotic protein Bax and p53.…”

Repair Process Impairment by Pseudomonas aeruginosa in Epithelial Tissues: Major Features and Potential Therapeutic Avenues

“…Accordingly, LPS from P. aeruginosa is frequently used in in vivo studies of induced acute lung injury. In vitro , it has been shown for example that LPS-exposed A549 (alveolar) and BEAS-2B (bronchial) cells display morphological changes, cell apoptosis and reduced cell survival (Cabrera-Benítez et al, 2016); these effects were attenuated by pyrrole compounds, which also dampened the inflammatory response. In addition, Yi et al showed that LPS induced a decrease in corneal transepithelial resistance, through tight junction disruption, by targeting ZO-1 and ZO-2 proteins (Yi et al, 2000).…”