Daily Respiratory Research Analysis

The lung is a highly vascularized organ in which endothelial cells (ECs) play a pivotal role in maintaining tissue homeostasis and regulating gas-blood exchange. Increasing evidence suggests that endothelial-to-mesenchymal transition (EndoMT) contributes to fibrosis; however, the underlying epigenetic mechanisms remain incompletely understood. Here, we identify disruptor of telomeric silencing 1-like (DOT1L), a histone H3 lysine 79 (H3K79) methyltransferase, as a key epigenetic regulator of EndoMT and fibrotic progression. In human umbilical vein ECs, TGFβ stimulation upregulated DOT1L expression and increased H3K79me2 levels during EndoMT. DOT1L knockdown abrogated H3K79 methylation and suppressed the expression of fibrosis-associated genes. Chromatin immunoprecipitation analysis revealed that direct binding of SMAD2 to the DOT1L promoter increased its transcription and promoted H3K79me2 deposition at fibrosis-related gene loci following TGFβ2 stimulation. In vivo, endothelial lineage-tracing in mice demonstrated H3K79me2 accumulation in ECs undergoing EndoMT during bleomycin-induced pulmonary fibrosis. Importantly, endothelial-specific deletion of Dot1L significantly attenuated fibrotic remodeling, collagen deposition, and mesenchymal marker expression. Collectively, these findings establish DOT1L as a critical epigenetic driver of EndoMT and pulmonary fibrosis through H3K79me2-mediated transcriptional activation, highlighting it as a potential therapeutic target in fibrotic lung disease.

Sarcoidosis is a systemic granulomatous disease that has limited treatment options. Emerging evidence suggests that macrophages are essential for sarcoid granuloma initiation. Legumain (LGMN), a cysteine protease, regulates macrophage polarization in various cancers. However, its involvement in sarcoid granuloma formation remains elusive. Herein, LGMN is upregulated in macrophages within sarcoid-like granulomas. Genetic deletion of Lgmn exacerbates granulomatous inflammation in a Propionibacterium acnes (P. acnes)-induced mouse model, accompanied by increased M1 macrophage polarization. Mechanistically, LGMN binds to integrin αvβ3 on the macrophage surface and restrains M1 polarization by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1)/signal transducer and activator of transcription 1 (STAT1) pathway. Furthermore, intratracheal administration of lipid nanoparticles carrying Lgmn plasmid DNA effectively alleviates granuloma formation induced by P. acnes or trehalose 6,6'-dimycolate, concomitant with decreased mTORC1/STAT1 activation and M1 polarization. These findings reveal the pivotal role of LGMN in restraining sarcoid granulomatous inflammation through suppression of mTORC1/STAT1-driven M1 macrophage polarization. Therefore, LGMN supplementation may be a promising therapeutic strategy for sarcoidosis.

BACKGROUND: Limited data exist concerning the impact of fixed-pressure PAP (FPAP) and auto-adjusting CPAP (APAP) on blood pressure (BP) in patients with obstructive sleep apnoea (OSA). RESEARCH QUESTION: In hypertensive patients with OSA, do FPAP and APAP lead to different effects on blood pressure? METHODS: In this double-blind, randomised crossover clinical trial, patients with OSA and hypertension were treated with both FPAP and APAP. Ambulatory blood pressure monitoring (ABPM) and autonomic function testing were performed before and after each treatment. The effect of PAP mode on the change from baseline (4-week value minus baseline value) was analysed using a Bayesian hierarchical linear model. RESULTS: Forty-six patients (mean age 48.8±11.2 years) with OSA (median AHI 59 [IQR: 34, 99] events/hour) were enrolled, with 30 patients completing both treatment arms. Median device use was 6.2 hours/night. In the primary Bayesian hierarchical analysis, FPAP showed a high probability of superior Systolic Blood Pressure (SBP) control compared to APAP. For 24-hour SBP, the posterior median treatment effect was -4.41 mmHg [95% CrI: -11.11, 2.00] with a Probability of Direction (pd) of 91.2%. This effect was more pronounced for nighttime SBP, with a posterior median change of -6.80 mmHg [95% CrI: -15.37, 1.76] and a pd of 94.0%. FPAP increased the likelihood of nocturnal diastolic BP dipping compared with APAP (posterior probability of benefit 94.3%; OR 4.09).Baseline characteristics, compliance, and satisfaction were similar between treatment sequences (pd typically < 75%). Mean FPAP pressure was higher than APAP (P95) pressures (12.51±4.55 vs. 10.33±2.66 cmH INTERPRETATION: Our analysis suggests a high probability that FPAP provides superior BP control compared to APAP in OSA patients with Hypertension. These findings challenge the assumption that APAP provides equivalent cardiovascular protection and suggest that fixed-pressure therapy, guided by manual titration, may be preferable for optimal blood pressure management in this population.