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Nintedanib ameliorates tracheal stenosis by activating HDAC2 and suppressing IL-8 and VEGF in rabbit.

ABSTRACT: Acquired tracheal stenosis is a common disease occurring after endotracheal intubation or tracheotomy. Currently, surgery is the main option to treat the stenosis. This study investigated therapeutic effect and possible mechanism of nintedanib on tracheal stenosis. The rabbit models of tracheal stenosis were established and were administered with nintedanib and budesonide. The damage and repair of the tracheal tissue were determined using hematoxylin and eosin (HE) staining. The expression of histone deacetylase 2 (HDAC2), interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) was detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western Blot and immunofluorescence assay. The expression of collagens I and III was assayed immunohistochemically. Remarkable tracheal stenosis was observed after the trachea was brushed in the rabbit model. Compared with control, the stenosis was improved after nintedanib treatment. The mRNA of HDAC2 was increased and that of IL-8 and VEGF was decreased significantly in the tracheal tissue following nintedanib treatment. Western blot analysis showed that HDAC2 increased to the level similar to that of control while VEGF remained unchanged following nintedanib treatment. Budesonide treatment also resulted in increased HDAC2 expression and decreased IL-8 and VEGF expression. Immunofluorescence assays also showed an increased HDAC2 expression following nintedanib treatment. Collagens I and III decreased significantly after nintedanib treatment in the tracheal tissues of models. Therefore, it is concluded that nintedanib alleviates the acquired tracheal stenosis by activating HDAC2 expression and suppressing IL-8 and VEGF expression, and may offer new option to medical treatment for the disease.

SUBMITTER: Wei P

PROVIDER: S-EPMC7476127 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Nintedanib ameliorates tracheal stenosis by activating HDAC2 and suppressing IL-8 and VEGF in rabbit.

Wei Peng P Huang Zhenjie Z Gan Luoman L Li Yu Y Qin Caicheng C Liu Guangnan G

American journal of translational research 20200815 8

Acquired tracheal stenosis is a common disease occurring after endotracheal intubation or tracheotomy. Currently, surgery is the main option to treat the stenosis. This study investigated therapeutic effect and possible mechanism of nintedanib on tracheal stenosis. The rabbit models of tracheal stenosis were established and were administered with nintedanib and budesonide. The damage and repair of the tracheal tissue were determined using hematoxylin and eosin (HE) staining. The expression of hi ...[more]

PMID: 32913546

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Project description:IntroductionPersistent neuroinflammatory response after cauda equina injury (CEI) lowers nociceptor firing thresholds, accompanied by pathological pain and decreasing extremity dysfunction. Histone deacetylation has been considered a key regulator of immunity, inflammation, and neurological dysfunction. Our previous study suggested that valproic acid (VPA), a histone deacetylase inhibitor, exhibited neuroprotective effects in rat models of CEI, although the underlying mechanism remains elusive.MethodsThe cauda equina compression surgery was performed to establish the CEI model. The Basso, Beattie, Bresnahan score, and the von Frey filament test were carried out to measure the animal behavior. Immunofluorescence staining of myelin basic protein and GPX4 was carried out. In addition, transmission electron microscope analysis was used to assess the effect of VPA on the morphological changes of mitochondria. RNA-sequencing was conducted to clarify the underlying mechanism of VPA on CEI protection.ResultsIn this current study, we revealed that the expression level of HDAC1 and HDAC2 was elevated after cauda equina compression model but was reversed by VPA treatment. Meanwhile, HDAC2 knockdown resulted in the improvement of motor functions and pathologic pain, similar to treatment with VPA. Histology analysis also showed that knockdown of histone deacetylase (HDAC)-2, but not HDAC1, remarkably alleviated cauda equina injury and demyelinating lesions. The potential mechanism may be related to lowering oxidative stress and inflammatory response in the injured region. Notably, the transcriptome sequencing indicated that the therapeutic effect of VPA may depend on HDAC2-mediated ferroptosis. Ferroptosis-related genes were analyzed in vivo and DRG cells further validated the reliability of RNA-sequencing results, suggesting HDAC2-H4K12ac axis participated in epigenetic modulation of ferroptosis-related genes.ConclusionHDAC2 is critically involved in the ferroptosis and neuroinflammation in cauda equina injury, and VPA ameliorated cauda equina injury by suppressing HDAC2-mediated ferroptosis.

Project description:BackgroundFisetin, the effective ingredient of the traditional Chinese medicine named Cotinus coggygria, is recommended to be active therapeutic in many disorders. However, its role in sepsis-associated encephalopathy (SAE) remains unclarified.MethodsCecal ligation and puncture (CLP) operation was performed to establish a rat model of SAE. Rats were grouped according to the surgery operation and fisetin administration. Cognitive impairment was assessed by Morris water maze test. Disruption of blood-brain barrier (BBB) integrity was detected by Evan's blue staining. The mitophagy, reactive oxygen species (ROS) generation, NLRP3 inflammasome activation, and pro-inflammatory cytokines levels were measured through western blot and double immunofluorescence labeling. A transmission electron microscope was applied for the observation of mitochondrial autophagosomes.ResultsRats in the CLP group presented increased expression of IL-1R1, pNF-κB, TNF-α, and iNOS in microglial cells, indicating severe inflammation in the central nervous system (CNS). Nevertheless, there was no increase in BBB permeability. Meanwhile, NLRP3 inflammasome was activated in cerebral microvascular endothelial cells (CMECs), presented with an elevation of caspase-1 expression and IL-1β secretion into CNS. In addition, we found fisetin significantly improved cognitive dysfunction in rats with SAE. Neuroprotective effects of fisetin might be associated with inhibition of neuroinflammation, represented with decreased expression of IL-1R1, pNF-κB, TNF-α, and iNOS in microglia. Furthermore, fisetin induced mitophagy, scavenged ROS, blocked NLRP3 inflammasome activation of CMECs, as evidenced by decreased expression of caspase-1 and reduced release of IL-1β into CNS.ConclusionCollectively, fisetin-blocked NLRP3 inflammasome activation via promoting mitophagy in CMECs may suppress the secretion of IL-1β into CNS, reduce neuroinflammation, and contribute to the amelioration of cognitive impairment.

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Nintedanib ameliorates tracheal stenosis by activating HDAC2 and suppressing IL-8 and VEGF in rabbit.

Publications

Nintedanib ameliorates tracheal stenosis by activating HDAC2 and suppressing IL-8 and VEGF in rabbit.

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