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Bronchopulmonary dysplasia (BPD) is a disease with a multi-factorial pathophysiology; however, current animal models lack complexity. We employed a double-hit model with an antenatal insult of foetal growth restriction paired with milder postnatal hyperoxia exposure. We induced foetal growth restriction (FGR) by injecting N(G)-nitro-L-arginine methyl ester (L-NAME) in the pregnant rabbit, and exposed preterm-born kittens to 70% hyperoxia for 7 days. L-NAME effectively induced FGR, and mortality rates were acceptable. The double-hit group exhibited adverse outcomes, including decreased lung compliance, increased airway resistance, and structural changes such as alveolar simplification and thickened septa. Gene expression analysis in the L-NAME group revealed downregulation of vascular growth factors, suggesting impaired vascular development. In contrast to traditional hyperoxia models, our double-hit approach enables lower hyperoxia exposure, aligning more closely with clinical practice guidelines in neonatology. The findings underscore the importance of antenatal factors in BPD pathophysiology and reinforce the need for refined animal models that accurately reflect the complexities of preterm lung development.

Background Bronchopulmonary dysplasia (BPD) is a chronic lung condition of premature neonates, yet without an established pharmacological treatment. The BPD rabbit model exposed to 95% oxygen has been used in recent years for drug testing. However, the toxicity of the strong hyperoxic hit precludes a longer-term follow-up due to high mortality after the first week of life. This study aimed to extend the preterm rabbit model to postnatal day (PND) 14 to mimic the evolving phase of BPD and enable the investigation of therapeutic interventions at later and more relevant time points. Methods Preterm rabbit pups delivered on the 28th day of gestation were either exposed to room air or different degrees of hyperoxia (50% and 70% O 2 ) for 14 days. Single (immediately after birth) or double (at birth and at PND5) intratracheal lipopolysaccharide (LPS) administrations were also tested in combination with 50% O 2 . Age-matched rabbits delivered vaginally at term were used as controls. Survival, weight gain, lung function, pulmonary artery micro-ultrasound Doppler analysis, lung histology (alveolarization, lung injury score, and design-based stereology), and longitudinal micro-CT imaging were used to compare the outcomes at PND14. Results Premature birth itself, without any other BPD hit, was associated with lung function deficits, delayed lung development, and cardiovascular abnormalities. The BPD-like lung phenotype was enhanced by 70% O 2 but not by 50% O 2 hyperoxia. Intratracheal LPS delivered immediately after birth was associated with significantly higher lung injury scores at PND14 and increased tissue damping, a marker of parenchymal air resistance. Conclusion Several strategies are feasible to extend the preterm rabbit model of BPD to PND14. Preterm birth at the saccular phase itself, even in the absence of other postnatal BPD hits, was associated with lung function deficits, delayed lung development, and cardiovascular abnormalities compared with age-matched term rabbit pups. Enhanced BPD-like phenotypes can be further achieved by continued exposure to moderate hyperoxia (70% O 2 ) and the intratracheal administration of LPS.

Thiazolidinediones (TZDs) are potent PPARγ agonists that have been shown to attenuate alveolar simplification after prolonged hyperoxia in term rodent models of bronchopulmonary dysplasia. However, the pulmonary outcomes of postnatal TZDs have not been investigated in preterm animal models. Here, we first investigated the PPARγ selectivity, epithelial permeability, and lung tissue binding of three types of TZDs in vitro (rosiglitazone (RGZ), pioglitazone, and DRF-2546), followed by an in vivo study in preterm rabbits exposed to hyperoxia (95% oxygen) to investigate the pharmacokinetics and the pulmonary outcomes of daily RGZ administration. In addition, blood lipids and a comparative lung proteomics analysis were also performed on Day 7. All TZDs showed high epithelial permeability through Caco-2 monolayers and high plasma and lung tissue binding; however, RGZ showed the highest affinity for PPARγ. The pharmacokinetic profiling of RGZ (1 mg/kg) revealed an equivalent biodistribution after either intratracheal or intraperitoneal administration, with detectable levels in lungs and plasma after 24 h. However, daily RGZ doses of 1 mg/kg did not improve lung function in preterm rabbits exposed to hyperoxia, and daily 10 mg/kg doses were even associated with a significant lung function worsening, which could be partially explained by the upregulation of lung inflammation and lipid metabolism pathways revealed by the proteomic analysis. Notably, daily postnatal RGZ produced an aberrant modulation of serum lipids, particularly in rabbit pups treated with the 10 mg/kg dose. In conclusion, daily postnatal RGZ did not improve lung function and caused dyslipidemia in preterm rabbits exposed to hyperoxia.

Background New onset refractory status epilepticus (NORSE) is a neurologic emergency without an immediately identifiable cause. The complicated and long ICU stay of the patients can lead to perceiving a prolongation of therapies as futile. However, a recovery is possible even in severe cases. This retrospective study investigates ICU treatments, short- and long-term outcome and ethical decisions of a case series of patients with NORSE. Methods Overall, 283 adults were admitted with status epilepticus (SE) to the Neurocritical Care Unit of the University Hospital Zurich, Switzerland, between 01.2010 and 12.2022. Of them, 25 had a NORSE. We collected demographic, clinical, therapeutic and outcome data. Descriptive statistics was performed. Results Most patients were female (68%), previously healthy (Charlson comorbidity index 1 [0–4]) and relatively young (54 ± 17 years). 96% presented with super-refractory SE. Despite extensive workup, the majority (68%) of cases remained cryptogenic. Most patients had a long and complicated ICU stay. The in-hospital mortality was 36% ( n  = 9). The mortality at last available follow-up was 56% ( n  = 14) on average 30 months after ICU admission. The cause of in-hospital death for 89% ( n  = 8) of the patients was the withholding/withdrawing of therapies. Medical staff except for one patient triggered the decision. The end of life (EOL) decision was taken 29 [12–51] days after the ICU admission. Death occurred on day 6 [1–8.5] after the decision was taken. The functional outcome improved over time for 13/16 (81%) hospital survivors (median mRS at hospital discharge 4 [3.75–5] vs. median mRS at last available follow-up 2 [1.75–3], p  < 0.001). Conclusions Our data suggest that the long-term outcome can still be favorable in NORSE survivors, despite a prolonged and complicated ICU stay. Clinicians should be careful in taking EOL decisions to avoid the risk of a self-fulfilling prophecy. Our results encourage clinicians to continue treatment even in initially refractory cases.