Dataset Information

Effects of dexmedetomidine on the expression profile of tsRNAs in LPS-induced acute lung injury.

ABSTRACT:

Background

Acute lung injury (ALI) is characterized by impaired alveolar function and excessive inflammation, which is commonly seen in clinical anesthesia and intensive care units. tRNA-derived small RNA (tsRNA) is a non-coding RNA that can be used as a potential disease diagnostic biomarker. The connection between ALI and tsRNA remains unknown. We aimed to explore the possible regulatory functions and mechanisms of tsRNAs in ALI treated with DEX.

Methods

Firstly, we established the ALI model by LPS injection and explored the effect of dexmedetomidine (DEX) treatment on lung damage. Then, the lung tissues were obtained from the LPS and LPS + DEX group for small RNA sequencing.

Results

We proved that DEX could ameliorate pulmonary injury, and decreased inflammation, pulmonary edema, and ferroptosis (MDA down-regulation and GPX4 up-regulation) in ALI. Furthermore, in the tsRNA expression profile, the top 10 down-regulated tsRNAs were tsRNA-1018, tsRNA-3045b, tsRNA-5021a, tsRNA-1020, tsRNA-5002b, tsRNA-3045b, tsRNA-1026, tsRNA-5004a, tsRNA-5005b and tsRNA-1009, and the top 10 up-regulated tsRNAs were tsRNA-3025b, tsRNA-3025a, tsRNA-5016b, tsRNA-3042b, tsRNA-3029b, tsRNA-3028b, tsRNA-5006a, tsRNA-3027b, tsRNA-3027a, and tsRNA-5009b. The enrichment analysis of GO terms and KEGG pathways pointed that target genes of DE-tsRNAs were mainly enriched in regulation of transcription-associated GO terms, NF-kappa B signaling pathway, MAPK signaling pathway, and PI3K-Akt signaling pathway. The RT-qPCR results of tsRNA-1020 and tsRNA-1018 were in accordance with small RNA sequencing data.

Conclusion

DEX affected the abnormal expression of tsRNAs in ALI. These aberrantly expressed tsRNAs and enriched physiological processes provide a scientific basis for the diagnosis and treatment of ALI.

SUBMITTER: Lin Y

PROVIDER: S-EPMC8761442 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAcute lung injury/acute respiratory distress syndrome (ALI/ARDS) are clinical syndromes characterized by acute lung inflammation, pulmonary edema and hypoxemia, with up to 50% mortality rate without effective pharmacological therapy. Following the acute inflammation, repair and remodeling occurs which in some cases resulting in lung fibrosis. The pathophysiology of ALI/ARDS remains incompletely understood. Lipopolysaccharide (LPS)-induced ALI in mice have been widely used as a model to study human ALI/ARDS. Isthmin 1 (ISM1) is a secreted protein highly abundant in mouse lung. We have previously reported that upon intratracheal LPS instillation, ISM1 expression in the lung is further upregulated. Recently, we also reported that ISM1 is an anti-inflammatory protein in the lung with Ism1-/- mice presenting spontaneous chronic low-grade lung inflammation and obvious emphysema at young adult stage. However, what role ISM1 plays in ALI/ARDS and lung fibrosis remain unclear.MethodsUsing Ism1-/- mice and intratracheal LPS-induced ALI, and local delivery of recombinant ISM1 (rISM1), we investigated the role ISM1 plays in ALI and post-ALI lung fibrosis using flow cytometry, Western blot, antibody array, immunohistochemistry (IHC), immunofluorescent and other histological staining.ResultsWe reveal that ISM1 deficiency in mice led to an intensified acute lung inflammation upon intratracheal LPS challenge, with a heightened leukocyte infiltration including neutrophils and monocyte-derived alveolar macrophages, as well as upregulation of multiple pro-inflammatory cytokines/chemokines including tumor necrosis factor α (TNF-α). Although innate immune cells largely subsided to the baseline by day 7 post-LPS challenge in both wild-type and Ism1-/- mice, Ism1-/- lung showed increased post-ALI fibrosis from day 9 post-LPS treatment with increased myofibroblasts, excessive collagen accumulation and TGF-β upregulation. The heightened lung fibrosis remained on day 28 post-LPS. Moreover, intranasal delivered recombinant ISM1 (rISM1) effectively suppressed LPS-induced acute lung inflammation and ALI, and rISM1 suppressed LPS-induced NF-κB activation in cultured mouse alveolar macrophages.ConclusionTogether with our previous report, this work further established ISM1 as an endogenous anti-inflammation protein in the lung, restraining excessive host inflammatory response to LPS-triggered ALI and suppressing post-ALI lung fibrosis likely through suppressing NF-κB activation and pro-inflammatory cytokine/chemokine production.