Respirology最新文献

Background and objective: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease driven by dysregulated alveolar epithelial cells (AECs) and fibroblasts. While aberrant p53 signalling contributes to IPF pathogenesis, the precise mechanism of p53 activation is not well understood. WDR63, a WD40-repeat protein implicated in lung cancer and male infertility, may be functionally relevant in IPF.

Methods: The mouse model of bleomycin-induced pulmonary fibrosis was used to investigate the role of WDR63 in IPF. Immunofluorescent staining and Western blotting assays were performed to assess WDR63 expression in samples from IPF patients and lungs from mice with bleomycin-induced fibrosis. Senescence-associated β-galactosidase (SA-β-gal) staining and flow cytometry assays were performed to evaluate the role of WDR63 in the senescence and apoptosis of AECs and lung fibroblasts. Mass spectrometry (MS) and immunoprecipitation were employed to identify potential substrate proteins of WDR63. Ubiquitination assays were utilised to elucidate the mechanisms of p53 stabilisation.

Results: WDR63 is significantly upregulated in IPF patients. WDR63 inhibits proliferation and migration while promoting senescence and apoptosis in AECs. In lung fibroblasts, WDR63 increases cellular senescence and facilitates their differentiation into myofibroblasts. WDR63 promotes K63-linked polyubiquitination of p53, while reducing its K48-linked polyubiquitination, thereby stabilising p53 and activating its downstream signalling. Ectopic WDR63 expression exacerbates bleomycin-induced pulmonary fibrosis in vivo, whereas WDR63 silencing attenuates fibrotic progression.

Conclusion: WDR63 stabilises p53 through K63-linked polyubiquitination, thereby driving pathological changes in AECs and lung fibroblasts and aggravating pulmonary fibrosis. These findings demonstrate that targeting WDR63 represents a novel therapeutic strategy for IPF.

Background and objective: The progression of pulmonary arterial hypertension (PAH) is associated with pulmonary artery (PA) remodelling by M2 macrophages through excessive tissue repair, although some M2 macrophages have a vascular protective role. A quality and quantity culture method (MNC-QQc) increases the number of M2 macrophages in mononuclear cells (MNCs) from peripheral blood. Several studies demonstrate that MNC-QQc has vascular protective effects in ischemic lesions. This study aimed to investigate whether MNC-QQc transplantation ameliorates PAH development in a rat model.

Methods: MNC-QQc extracted from GFP positive donor rats were administered into recipient rats with PAH via the cervical vein. Pulmonary haemodynamics and PA remodelling were assessed. Immunohistochemistry and flow cytometry analysis were performed to identify the donor-derived MNC-QQc cell types in the lungs. The effects of MNC-QQc on the functions of vascular constituent cells were evaluated, and gene expression related to the pathological abnormalities in PA was assessed using microarray analysis.

Results: MNC-QQc transplantation reversed the PAH-induced pulmonary haemodynamics and PA remodelling. GFP-positive MNC-QQc cells, predominantly CD14-positive M2 macrophages, were found around the recipient's PAs. The therapeutic effect was reduced in MNC-QQc without M2 cells. MNC-QQc also enhanced angiogenesis in pulmonary endothelial cells. Microarray analysis of the lung tissue showed that MNC-QQc decreased the expression of Tachykinin Receptor 1, associated with PAH progression, with this reduction linked to CD14- and CD163-positive M2 macrophages.

Conclusions: These findings suggest that MNC-QQc, particularly through CD14- and CD163-positive M2 macrophages, could be a novel treatment for PAH.

Background and objective: Adults with bronchiectasis often present with altered body composition and muscle strength, yet prognostic value of peripheral muscle strength are not well understood. This study compared body composition and muscle function between adults with bronchiectasis and healthy controls and examined whether peripheral muscle strength estimates one-year clinical outcomes.

Methods: Adults with HRCT-confirmed bronchiectasis and controls underwent assessments including DXA (body composition), dynamometry (leg and shoulder strength), and core endurance tests. Participants with bronchiectasis were classified as having retained or impaired leg strength based on the 10^th percentile of control values and were reassessed after one year for exacerbations, dyspnoea, quality of life, anxiety and depression, and exercise capacity.

Results: Seventy-one participants with bronchiectasis and 92 controls were included; 43 bronchiectasis participants completed follow-up. Females with bronchiectasis had lower appendicular muscle index (p = 0.018) and both sexes had lower bone mineral density compared to their control counterparts (p < 0.001). Osteopenia was 3 times more prevalent in females with bronchiectasis compared to their counterparts (54% versus 18%). Females with bronchiectasis have poorer lateral core endurance than those without (p ≤ 0.003). Leg strength was reduced in bronchiectasis compared to controls, regardless of sex (mean difference [95% CI] for males -25 [-50; -1] Kg and females -18 [-29; -7] Kg). Reduced leg strength is associated with worse dyspnoea, health related quality of life, and functional capacity over one year, explaining up to 33% of the variance (p ≤ 0.001).

Conclusion: Individuals with bronchiectasis exhibit impaired muscle function and bone health, with leg strength showing a significant association with clinical outcomes over one year.

Background and objective: Sympathetic nerve activity is heightened in pulmonary arterial hypertension (PAH), promotes deleterious pulmonary vascular and right ventricular remodelling, and is associated with worsened exercise capacity and mortality. Pulmonary arterial baroreceptors, activated by increased pulmonary arterial pressure and distension, could drive muscle sympathetic nerve activity (MSNA) in pulmonary hypertension (PH). We hypothesised that pulmonary arterial baroreceptor unloading using nebulised iloprost as a pulmonary arterial vasodilator would lower MSNA in clinically stable treated PAH and chronic thromboembolic PH (CTEPH) patients.

Methods: In eleven PH patients (9 PAH, 2 CTEPH; 6 female; age 54 ± 14 years) common peroneal nerve microneurography was performed to record MSNA (n = 9) at baseline (10 min) and immediately following iloprost nebulisation (10 min). Concurrent measures of cardiorespiratory physiology and pulmonary haemodynamics (transthoracic echocardiography) were obtained.

Results: Iloprost reduced systolic pulmonary artery pressure (50 ± 19 mmHg baseline vs. 44 ± 15 mmHg iloprost; p = 0.040), and increased right ventricular outflow tract acceleration time (RVOT AT; 99 ± 15 ms baseline vs. 117 ± 16 ms iloprost; p < 0.001). Although no overall change was seen in MSNA (p > 0.05), the magnitude of change in MSNA burst size was inversely associated with the increase in RVOT AT (R² = 0.667, p = 0.0133).

Conclusion: These findings provide evidence suggestive of possible pulmonary arterial baroreceptor influence of MSNA burst amplitude in some PH patients. Pulmonary arterial baroreceptor activation may be a contributory mechanism to adverse sympatho-excitation in PH.

Clinical trial registration: ACTRN12622000494730.

Background and objective: Peripheral blood cell counts are useful biomarkers in COPD, but may not fully reflect disease activity. The Sysmex XN-Series haematology analyser offers advanced measurements of immune cell populations, providing information about the number and activation status of peripheral blood cells. We hypothesized that assessing immune cell activation status, in addition to cell counts, could provide complementary insights into the clinical heterogeneity of severe COPD.

Methods: For this study, 499 extensively characterised patients with severe COPD were included from the Groningen Severe COPD cohort. A total of 24 Sysmex-derived systemic blood parameters were selected for analysis. Clustering of blood cell population data was performed using Self-Organising Maps.

Results: The cell population parameters showed various associations with clinical characteristics, such as emphysema severity and lung function. Four clusters were identified based on their inflammatory profiles, each showing distinct clinical characteristics: the 'normal cell counts, resting pattern' cluster (n = 156) showed high emphysema severity scores and RV/TLC ratios; the 'normal cell counts, activated pattern' cluster (n = 241) was associated with few exacerbations; the 'elevated cell counts, activated pattern' cluster (n = 97) displayed high inflammatory cell counts and activity along with high exacerbation rates; and the small 'low-eosinophilic' cluster (n = 5) was characterised by inactive circulating eosinophils.

Conclusion: Cell population data can be used to identify distinct inflammatory profiles with clinical relevance in severe COPD. Cell population data provide information beyond absolute cell counts, supporting the added value of including activation markers in COPD phenotyping.

Trial registration: NCT04023409 at clinicaltrials.gov.

Background and objective: Fixed CPAP (fCPAP) is the preferred first-line ventilatory therapy in patients with obesity hypoventilation syndrome with severe obstructive sleep apnoea (OHS + sOSA). Auto-titrating CPAP (APAP) is not recommended but has not been systematically evaluated in this population. Our pilot study aimed to provide feasibility data for a larger comparative effectiveness trial to determine whether APAP is non-inferior to fCPAP for improving hypercapnic respiratory failure.

Methods: Participants with OHS + sOSA were randomised to either APAP or fCPAP for 3 months. The primary outcome was the change in PaCO₂. Secondary outcomes included changes in quality of life and cardiovascular biomarkers. A sample size of 82 was needed to demonstrate non-inferiority of APAP compared to fCPAP (assuming a non-inferiority margin of -2.5 mmHg). To assess feasibility we aimed to recruit up to 44 participants in this pilot trial.

Results: Twenty-eight of 84 screened participants were randomised (Mean ± SD: Age 55 ± 12.5 years, BMI 54 ± 9.9 kg m^-2, PaCO₂ 49 ± 2.6 mmHg, AHI 88 ± 31 events/h) to APAP (n = 15) or fCPAP (n = 13). Mean adherence exceeded 4 h in both groups; however 25% of randomised participants did not complete the trial. Both treatments reduced PaCO₂ (fCPAP: -5.7 ± 1.6 mmHg, APAP: -4.1 ± 2.8 mmHg). Test of non-inferiority for APAP versus fCPAP was inconclusive (mean ΔPaCO₂ difference = -1.7 mmHg (95% CI -5.0 to 1.6 mmHg)). Adherence and sleep quality improvements favoured fCPAP, while other outcomes were comparable.

Conclusion: The pilot study highlighted important challenges with recruitment and retention. While the study is not powered to confirm the non-inferiority of APAP, some outcomes appeared to favour fCPAP and APAP use in OHS + sOSA should be approached cautiously. A larger study with protocol modifications is required to confirm these preliminary findings.

Trial registration: ACTRN12618000379213. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374259. Assessing the Efficacy of Auto-titrating versus Fixed Continuous Positive Airway Pressure in Obesity Hypoventilation Syndrome.