Pathological Insight into 5-HT2B Receptor Activation in Fibrosing Interstitial Lung Diseases

Löfdahl, Anna; Tornling, Göran; Wigén, Jenny; Larsson‐Callerfelt, Anna Karin; Wenglén, Christina; Westergren‐Thorsson, Gunilla

doi:10.3390/ijms22010225

Cited by 17 publications

(9 citation statements)

References 143 publications

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“…Basic studies have shown that 5-HT receptor antagonists can protect the lungs. For example, they attenuated ischemia-reperfusion injury after lung preservation in a rabbit model ( 10 ), and also reduced myofibroblast differentiation and connective tissue deposits in fibrosing interstitial lung diseases ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Association between ondansetron use and mortality of patients on mechanical ventilation in the intensive care unit: a retrospective cohort study

Tao¹,

Chen²,

Chang³

et al. 2023

Ann Transl Med

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Background Basic studies show that selective 5-hydroxytryptamine type 3 (5-HT 3 ) serotonin-receptor antagonists can protect organs from inflammatory injury and have shown lung protection. Whether 5-HT 3 receptor antagonists ondansetron benefits patients with mechanical ventilation is unclear in the intensive care unit (ICU). Methods The Medical Information Mart for Intensive Care-IV (MIMIC-IV) database was reviewed to identify patients on mechanical ventilation (aged >16 years) in the ICU, which was divided into two groups according to whether ondansetron is used. Demographic characteristics, medical history data, clinical parameters, diagnosis and treatment measures were included as covariates. Ondansetron use was defined as any kind of ondansetron administration regardless of the dose before the induction of mechanical ventilation. The primary outcome was in-hospital death. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated by multivariable Cox regression. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to further adjust for confounding factors. Kaplan-Meier (KM) curves with log-rank test were also performed. Results A total of 18,566 patients on mechanical ventilation were included (5,735 with ondansetron use). The overall in-hospital mortality rate of patients on mechanical ventilation was 18.9% (3,512/18,566). Approximately 13.0% (746/5,735) and 21.6% (2,766/12,831) in-hospital mortality rates occurred in the ondansetron and non-ondansetron use groups, respectively. Multivariable regression indicated that ondansetron usage was associated with a 33% and 32% lower risk of in-hospital and 60-day death (HR =0.77, 95% CI: 0.70–0.85, P<0.001; HR =0.68, 95% CI: 0.62–0.75, P<0.001) in the whole sample. Multivariable regression post-PSM indicated that ondansetron usage was associated with a 38% and 31% lower risk of in-hospital and 60-day death (HR =0.62, 95% CI: 0.56–0.68, P<0.001; HR =0.69, 95% CI: 0.62–0.77, P<0.001). Log-rank test for the KM curve of ondansetron and 60-day death was statistically significant (P<0.001). The duration of ventilator use pre- and post-PSM was statistically different (P<0.001 and P=0.007) in the two groups. Conclusions Ondansetron usage was significantly associated with a lower mortality risk of ventilated patients in the ICU. The 5-HT3 receptor antagonist use is may be new potential adjunctive therapeutic strategy for patients on mechanical ventilation in the ICU.

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Section: Introductionmentioning

confidence: 99%

Association between ondansetron use and mortality of patients on mechanical ventilation in the intensive care unit: a retrospective cohort study

Tao¹,

Chen²,

Chang³

et al. 2023

Ann Transl Med

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“…The mortality of mechanically ventilated patients is high at 30% 1,2 . It has been suggested that 5‐hydroxytryptamine (5‐HT) plays a role in the pathophysiology of a wide range of diseases and conditions, including chronic obstructive pulmonary disease (COPD), 3,4 myocardial infarction, 5 adult respiratory distress syndrome, 6 sepsis, 7 lung ischemia–reperfusion injury, 8 pulmonary arterial hypertension, 9–12 interstitial lung diseases, 13 non‐small‐cell lung cancer and lung adenocarcinoma 14–16 . 5‐HT is an inflammatory mediator released in the lung 17 .…”

Section: Introductionmentioning

confidence: 99%

Mediators of neutrophil–lymphocyte ratio in the relationship between ondansetron pre‐treatment and the mortality of ICU patients on mechanical ventilation: Causal mediation analysis from the MIMIC‐IV database

Zhou

Tao

Zhang

et al. 2022

Brit J Clinical Pharma

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Aims The mortality of critically ill patients undergoing mechanical ventilation (MV) is high and few strategies are available. We explored the relationship between ondansetron pre‐treatment, the neutrophil–lymphocyte ratio (NLR), and platelet–lymphocyte ratio (PLR), and mortality of ventilated patients in the intensive care unit. Methods We developed a retrospective cohort study that involved patients undergoing MV in the Multiparameter Intelligent Monitoring in Intensive Care IV (MIMIC‐IV) database. Causal mediation analysis was conducted to assess the relationship of ondansetron use and mortality and to explore the potential causal pathway mediated by the NLR or PLR. The primary outcome was 28‐day mortality. Results A total of 17 927 eligible patients took part in the study (5665 had taken ondansetron before MV initiation and 12 262 patients had not). The odds ratio (OR) for 28‐day mortality for ondansetron use uncorrelated with the mediator (NLR, PLR) was 0.72 (95% confidence interval [CI] = 0.64–0.81, P < .001). Ondansetron was also associated with a reduction in 28‐day mortality after controlling for the mediator of NLR (OR = 0.98, 95% CI = 0.97–0.99, P < .01). For the indirect effect, the NLR could explain 13.47% (95% CI = 8.59–20.54%, P < .01) of the impact of ondansetron use on 28‐day mortality. The proportion mediated increased to 21.50% (95% CI = 12.36–47.44%, P < .01) for 90‐day mortality. Adjusted mediation analysis revealed no suggestion of a causal mediation pathway for this effect by the PLR (P = .12). Conclusions NLR may play substantial roles in the relationship between ondansetron pre‐treatment before initiation of mechanical ventilation and the reduction of death risk in ventilated patients.

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“… 29 It was shown an enhanced activation of serotonergic signaling in pulmonary fibrosis, and the serotonin (5-HT)2 receptors have been implicated to have important roles in observed profibrotic actions. 32 Thus, dopamine receptor antagonists might have the potential to stimulate angiogenesis and therefore represent a novel approach to tackle COPD.…”

Section: Introductionmentioning

confidence: 99%

Spiperone Stimulates Regeneration in Pulmonary Endothelium Damaged by Cigarette Smoke and Lipopolysaccharide

Скурихин¹,

Першина²,

Zhukova³

et al. 2021

COPD

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Background Endothelial dysfunction and destruction of the pulmonary microcirculation are important pathogenic factors in chronic obstructive pulmonary disease (COPD). In COPD, bronchial obstruction is associated with endothelial dysfunction. Thus, new pharmacological treatment options aimed at restoring the pulmonary endothelium represent a clinical need in COPD therapy. Notch1 has been shown to protect cells against apoptosis, inflammation, and oxidative stress caused by cigarette smoke extract (CSE). Therefore, drug which effect on Notch1 may be a potential therapeutic target for COPD in the future. Methods In this study, we assessed the potential of spiperone to mediate regeneration of pulmonary endothelium in model of pulmonary emphysema induced by a CSE and lipopolysaccharide (LPS) in female C57BL/6 mice. Results Spiperone increased the number of capillaries as well as the expression of the CD31 in the alveolar tissue compared to the controls. Moreover, application of spiperone prevented alveolar wall destruction (DI), and reduced the area of emphysema. Lastly, we demonstrated that spiperone positively influenced mobilization and migration of endothelial progenitor cells (EPC, CD45 − CD34 + CD31 + ), CD309 + -endothelial cells, and angiogenesis precursors (CD45 − CD117 + CD309 + ) into the lung. Spiperone administration significantly reduced the number Notch1 positive CD309 + -endothelial cells and Notch1+ EPCs. Conclusion Overall, our results suggest that spiperone mediates endothelial regeneration in an animal model of COPD. Thus, it could represent a novel therapeutic approach for treatment of emphysema associated with COPD.

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Pathological Insight into 5-HT2B Receptor Activation in Fibrosing Interstitial Lung Diseases

Cited by 17 publications

References 143 publications

Association between ondansetron use and mortality of patients on mechanical ventilation in the intensive care unit: a retrospective cohort study

Association between ondansetron use and mortality of patients on mechanical ventilation in the intensive care unit: a retrospective cohort study

Mediators of neutrophil–lymphocyte ratio in the relationship between ondansetron pre‐treatment and the mortality of ICU patients on mechanical ventilation: Causal mediation analysis from the MIMIC‐IV database

Spiperone Stimulates Regeneration in Pulmonary Endothelium Damaged by Cigarette Smoke and Lipopolysaccharide

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