Fibroblast-derived extracellular vesicles contain SFRP1 and mediate pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal chronic lung disease characterized by aberrant intercellular communication, extracellular matrix deposition, and destruction of functional lung tissue. While extracellular vesicles (EVs) accumulate in the IPF lung, their cargo and biological effects remain unclear. We interrogated the proteome of EV and non-EV fractions during pulmonary fibrosis and characterized their contribution to fibrosis. EVs accumulated 14 days after bleomycin challenge, correlating with decreased lung function and initiated fibrogenesis in healthy precision-cut lung slices. Label-free proteomics of bronchoalveolar lavage fluid EVs (BALF-EVs) collected from mice challenged with bleomycin or control identified 107 proteins enriched in fibrotic vesicles. Multiomic analysis revealed fibroblasts as a major cellular source of BALF-EV cargo, which was enriched in secreted frizzled related protein 1 (SFRP1). Sfrp1 deficiency inhibited the activity of fibroblast-derived EVs to potentiate lung fibrosis in vivo. SFRP1 led to increased transitional cell markers, such as keratin 8, and WNT/ß-catenin signaling in primary alveolar type 2 cells. SFRP1 was expressed within the IPF lung and localized at the surface of EVs from patient-derived fibroblasts and BALF. Our work reveals altered EV protein cargo in fibrotic EVs promoting fibrogenesis and identifies fibroblast-derived vesicular SFRP1 as a fibrotic mediator and potential therapeutic target for IPF.

Real-life evaluation of NIV to CPAP switch in patients with chronic respiratory failure. A case control study.

BACKGROUND: Non-invasive ventilation (NIV) is a standard of care for hypercapnic chronic respiratory failure (CRF). Obstructive sleep apnea syndrome (OSA) frequently contributes to hypoventilation in CRF patients. CPAP improves hypercapnia in selected COPD and obese patients, like NIV. We aimed to describe the profile of patients switching from NIV to CPAP in a cohort of patients on long-term ventilation and to identify the factors associated with a successful switch. METHODS: In this case-control study, 88 consecutive patients who were candidates for a NIV-CPAP switch were compared with 266 controls among 394 ventilated patients treated at the Dijon University Hospital between 2015 and 2020. They followed a standardized protocol including a poly(somno)graphy recorded after NIV withdrawal for three nights. CPAP trial was performed if severe OSA was confirmed. Patients were checked for recurrent hypoventilation after 1 and 23[14-46] nights under CPAP. RESULTS: Patients were 53% males, median age 65 [56-74] years, and median BMI 34 [25-38.5] kg/m2. Sixty four percent of patients were safely switched and remained on long-term CPAP. In multivariate analysis, the probability of a NIV-CPAP switch was correlated to older age (OR: 1.3 [1.01-1.06]), BMI (OR: 1.7 [1.03-1.12]), CRF etiology (OR for COPD: 20.37 [4.2-98,72], OR for obesity: 7.31 [1.58-33.74]), circumstances of NIV initiation (OR for acute exacerbation: 11.64 [2.03-66.62]), lower pressure support (OR: 0.90 [0.73-0.92]), lower baseline PaCO2 (OR: 0.85 [0.80-0.91]) and lower compliance (OR: 0.76 [0.64-0.90]). Among 72 patients who went home under CPAP, pressure support level was the only factor associated with the outcome of the NIV-CPAP switch, even after adjustment for BMI and age (p=0.01) with a non-linear correlation. Etiology of chronic respiratory failure, age, BMI, baseline PaCO2, circumstances of NIV initiation, time under home NIV or NIV compliance were not predictive of the outcome of the NIV-CPAP switch. CONCLUSIONS: A NIV-CPAP switch is possible in real life conditions in stable obese and COPD patients with underlying OSA.

Characteristics and outcomes of gemcitabine-associated pulmonary hypertension.

Background: Despite its known cardiac and lung toxicities, the chemotherapy drug gemcitabine has only rarely been associated with pulmonary hypertension (PH), and the underlying mechanism remains unclear. The objective of the present study was to assess the association between gemcitabine and PH. Methods: We identified incident cases of precapillary PH confirmed by right heart catheterisation in patients treated with gemcitabine from the French PH Registry between January 2007 and December 2022. The aetiology, clinical, functional, radiological and haemodynamic characteristics of PH were reviewed at baseline and during follow-up. A pharmacovigilance disproportionality analysis was conducted using the World Health Organization (WHO) pharmacovigilance database. Results: We identified nine cases of pulmonary arterial hypertension, either induced (in eight patients) or exacerbated (in one patient) by gemcitabine. Patients exhibited severe precapillary PH, with a median mean pulmonary arterial pressure of 40 (range 26-47) mmHg, a cardiac index of 2.4 (1.6-3.9) L·min-1·m-2 and a pulmonary vascular resistance of 6.3 (3.1-12.6) Wood units. The median time from the initiation of gemcitabine to the onset of PH was 7 (4-50) months, with patients receiving a median of 16 (6-24) gemcitabine injections. Six patients showed clinical improvement upon discontinuation of gemcitabine. In the WHO pharmacovigilance database, we identified a significant signal with 109 cases reporting at least one adverse event related to PH with gemcitabine. Conclusion: Both clinical cases and pharmacovigilance data substantiate a significant association between gemcitabine use and the onset or worsening of precapillary PH. The observed improvement following the discontinuation of treatment underscores the importance of PH screening in gemcitabine-exposed patients experiencing unexplained dyspnoea.

Residual upper airway obstruction during nocturnal noninvasive ventilation despite high positive expiratory pressure. Impact of oronasal mask to nasal mask switch.

BACKGROUND: Nasal mask (NM) and oronasal masks (OM) can be used to provide noninvasive ventilation (NIV). Recent studies suggested that OM is the most used interface and that there is no difference in efficacy or in tolerance between OM and NM for chronic use. However, studies focusing on video laryngoscopy underlined the impact of OM in residual upper airway obstruction (UAO) under NIV. We sought to assess the real-life practice of switching from OM to NM when UAO events persist despite high EPAP levels. METHODS: In an open-label single center prospective cohort study, data from files and full night polysomnography on NM and OM were collected for patients wearing OM and presenting an UAO index ≥15/h despite an EPAP level ≥ 10 cmH20. RESULTS: Forty-four patients were included in the study. In 31 patients (74 %), switching to a NM reduced UAOi to ≥10/h. Interestingly, 92 % of these patients still had NM at 3 to 12 months of follow-up. Switching to a NM was also associated with a trend in paCO2 reduction and significant improvements in Epworth, sleep quality and NIV compliance. Successful interface switching was significantly associated with female gender, and a trend was observed in non-smokers. CONCLUSION: As for CPAP, switching to a NM improved NIV efficacy in a selected group of patients presenting residual UAO events despite high EPAP levels. Additionally, this switch has an impact on compliance and subjective sleepiness. Thus, in patients with persisting UAO on OM, switching to a NM could be a first-line intervention before considering further investigation such as polygraphy or video laryngoscopy. We also derive an algorithm for mask allocation and adaptation in acute and chronic NIV use.