Res Sq. 2023 Dec 18:rs.3.rs-3676579. doi: 10.21203/rs.3.rs-3676579/v1. Preprint.

ABSTRACT

Human diseases are characterized by intricate cellular dynamics. Single-cell sequencing provides critical insights, yet a persistent gap remains in computational tools for detailed disease progression analysis and targeted in-silico drug interventions. We introduce UNAGI, a deep generative neural network tailored to analyze time-series single-cell transcriptomic data. This innovative tool captures the complex cellular dynamics underlying disease progression, enhancing drug perturbation modeling and discovery. When applied to a dataset from patients with Idiopathic Pulmonary Fibrosis (IPF), UNAGI adeptly learns disease-informed cell embeddings that sharpen our understanding of disease progression, leading to the identification of potential therapeutic drug candidates. Validation via proteomics reveals the accuracy of UNAGI's cellular dynamics analyses, and the use of the Fibrotic Cocktail treated human Precision-cut Lung Slices confirms UNAGI's predictions that Nifedipine, an antihypertensive drug, may have antifibrotic effects on human tissues. UNAGI's versatility extends to other diseases, including a COVID dataset, demonstrating adaptability and confirming its broader applicability in decoding complex cellular dynamics beyond IPF, amplifying its utility in the quest for therapeutic solutions across diverse pathological landscapes.

PMID:38196613 | PMC:PMC10775382 | DOI:10.21203/rs.3.rs-3676579/v1

Sci Rep. 2024 Jan 9;14(1):859. doi: 10.1038/s41598-023-49459-6.

ABSTRACT

Hypersensitivity Pneumonitis (HP) is an immune-mediated interstitial lung disease (ILD) characterized by fibrotic HP (fHP) or non-fibrotic HP (non-fHP). Fibrosis is associated with poor prognosis, emphasizing the need for biomarkers to distinguish fHP from non-fHP. This study aimed to determine the plasma levels of GDF15 in HP patients and assess its association with lung function and phenotype classification. GDF15 levels were quantified by ELISA in HP (n = 64), idiopathic pulmonary fibrosis (n = 54), and healthy control (n = 128) groups. Clinical, demographic, and functional data were obtained from medical records. High-resolution chest CT scans were used to classify HP patients into fHP and non-fHP groups. In addition, receiver operating characteristic analysis was performed to determine the cut-off point, sensitivity, and specificity. Our results revealed significantly elevated GDF15 levels in fHP compared to non-fHP (2539 ± 821 pg/ml versus 1783 ± 801 pg/ml; p = 0.009). The estimated cut-off point for plasma GDF15 levels to distinguish fHP from non-fHP was 2193.4 pg/ml (AUC 0.75). These findings suggest that GDF15 may serve as a valuable biomarker for differentiating between fHP and non-fHP, potentially indicating its involvement in lung fibrosis development in HP.

PMID:38195721 | DOI:10.1038/s41598-023-49459-6

J Korean Med Sci. 2024 Jan 8;39(1):e13. doi: 10.3346/jkms.2024.39.e13.

ABSTRACT

BACKGROUND: Neutrophilic inflammation is a characteristic feature of idiopathic pulmonary fibrosis (IPF). S100 calcium-binding protein A9 (S100A9) is a neutrophil-derived protein involved in the development of neutrophil-related chronic inflammatory disorders. However, the role of S100A9 in IPF remains unclear.

METHODS: We used enzyme-linked immunosorbent assays to measure S100A9 levels in bronchoalveolar lavage fluid (BALF) and serum obtained from healthy controls (HCs) and patients with IPF, non-specific interstitial pneumonia, hypersensitivity pneumonitis, and sarcoidosis.

RESULTS: Compared with HCs, BALF S100A9 levels were significantly higher in IPF patients (P < 0.001), patients with hypersensitivity pneumonitis (P = 0.043), and patients with nonspecific interstitial pneumonia (P < 0.001). The S100A9 level in BALF of 0.093 ng/mL could distinguish IPF patients from HCs, with a specificity of 78.8% and a sensitivity of 81.6%. Similarly, the S100A9 level in BALF of 0.239 ng/mL had a specificity of 64.7% and a sensitivity of 66.7% for distinguishing IPF patients from patients with other interstitial lung diseases. Additionally, BALF S100A9 levels were significantly correlated with neutrophil counts (r = 0.356, P < 0.001) in BALF. IPF patients with S100A9 levels in BALF > 0.533 ng/mL had lower survival rates, compared with patients who had levels ≤ 0.553 ng/mL (n = 49; hazard ratio [HR], 3.62; P = 0.021). Combination analysis revealed that IPF patients with S100A9 levels in BALF> 0.553 ng/mL or neutrophil percentages > 49.1% (n = 43) had significantly lower survival rates than patients with S100A9 levels in BALF ≤ 0.553 ng/mL and neutrophil percentages ≤ 49.1% (n = 41) (HR, 3.91; P = 0.014). Additionally, patients with serum S100A9 levels > 0.077 ng/mL (n = 29) had significantly lower survival rates than patients with levels ≤ 0.077 ng/mL (n = 53, HR, 2.52; P = 0.013). S100A9 was expressed on neutrophils and macrophages in BALF from IPF patients as well as α-smooth muscle actin positive cells in the lung tissues.

CONCLUSION: S100A9 is involved in the development and progression of IPF. Moreover, S100A9 levels in BALF and serum may be surrogate markers for IPF diagnosis and survival prediction, particularly when analyzed in combination with neutrophil percentages.

PMID:38193329 | DOI:10.3346/jkms.2024.39.e13

Front Pharmacol. 2023 Dec 12;14:1301923. doi: 10.3389/fphar.2023.1301923. eCollection 2023.

ABSTRACT

Background: Recent studies have suggested that combination therapy with pirfenidone and nintedanib is safe and tolerable in patients with idiopathic pulmonary fibrosis (IPF). However, data from real-world practice are limited. Thus, we aimed to investigate the safety and efficacy of this combination therapy in patients with IPF in a real-world setting. Methods: A multicenter retrospective cohort study was conducted to investigate the safety and efficacy of combination therapy with pirfenidone and nintedanib in 45 patients with IPF. Incidences of adverse events and rates of lung function decline were compared before and after the combination therapy. Propensity score matching was performed to compare the outcomes between the combination and monotherapy groups. Results: The mean age of the patients was 68.8 years, and 82.2% of them were male. The median follow-up duration after combination therapy was 12.1 months. The majority of the patients (97.8%) received nintedanib as an add-on to pirfenidone. The most common adverse events after the combination therapy were diarrhea and anorexia. Pirfenidone or nintedanib was stopped in 12 patients owing to gastrointestinal AEs, lung transplantation, or financial problems. In patients with serial lung function data, the rate of decline in the forced vital capacity was significantly reduced after the combination therapy. In the matched analysis, the combination group had a higher incidence of diarrhea than the monotherapy group without an increase in serious adverse events; however, the two groups had similar changes in forced vital capacity (FVC). Conclusion: The combination of pirfenidone and nintedanib in patients with IPF has the potential to reduce the rate of FVC decline. However, in the matched analysis, FVC decline was comparable between the patients on combination therapy and those on monotherapy. The incidence of certain adverse events, particularly diarrhea, was higher with combination therapy, but serious adverse events were similar between the groups.

PMID:38192410 | PMC:PMC10773730 | DOI:10.3389/fphar.2023.1301923

PLOS Digit Health. 2024 Jan 8;3(1):e0000318. doi: 10.1371/journal.pdig.0000318. eCollection 2024 Jan.

ABSTRACT

INTRODUCTION: Patients diagnosed with Interstitial Lung Diseases (ILD) use devices to self-monitor their health and well-being. Little is known about the range of devices, selection, frequency and terms of use and overall utility. We sought to quantify patients' usage and experiences with home digital devices, and further evaluate their perceived utility and barriers to adaptation.

METHODS: A team of expert clinicians and patient partners interested in self-management approaches designed a 48-question cross-sectional electronic survey; specifically targeted at individuals diagnosed with ILD. The survey was critically appraised by the interdisciplinary self-management group at Royal Devon University Hospitals NHS Foundation Trust during a 6-month validation process. The survey was open for participation between September 2021 and December 2022, and responses were collected anonymously. Data were analysed descriptively for quantitative aspects and through thematic analysis for qualitative input.

RESULTS: 104 patients accessed the survey and 89/104 (86%) reported a diagnosis of lung fibrosis, including 46/89 (52%) idiopathic pulmonary fibrosis (IPF) with 57/89 (64%) of participants diagnosed >3 years and 59/89 (66%) female. 52/65(80%) were in the UK; 33/65 (51%) reported severe breathlessness medical research council MRC grade 3-4 and 32/65 (49%) disclosed co-morbid arthritis or joint problems. Of these, 18/83 (22%) used a hand- held spirometer, with only 6/17 (35%) advised on how to interpret the readings. Pulse oximetry devices were the most frequently used device by 35/71 (49%) and 20/64 (31%) measured their saturations more than once daily. 29/63 (46%) of respondents reported home-monitoring brought reassurance; of these, for 25/63 (40%) a feeling of control. 10/57 (18%) felt it had a negative effect, citing fluctuating readings as causing stress and 'paranoia'. The most likely help-seeking triggers were worsening breathlessness 53/65 (82%) and low oxygen saturation 43/65 (66%). Nurse specialists were the most frequent source of help 24/63 (38%). Conclusion: Patients can learn appropriate technical skills, yet perceptions of home-monitoring are variable; targeted assessment and tailored support is likely to be beneficial.

PMID:38190384 | DOI:10.1371/journal.pdig.0000318

Am J Physiol Cell Physiol. 2024 Jan 8. doi: 10.1152/ajpcell.00563.2023. Online ahead of print.

ABSTRACT

Mast-Cell Expressed Membrane Protein-1 (MCEMP1) is higher in Idiopathic Pulmonary Fibrosis (IPF) patients with increased risk of death. Here we aimed to establish the mechanistic role of MCEMP1 in pulmonary fibrosis. We identified increased MCEMP1 expression in classical monocytes and alveolar macrophages in IPF compared to controls. MCEMP1 was upregulated by TGFβ at the mRNA and protein levels in THP-1. TGFβ-mediated MCEMP1 upregulation results from the cooperation of SMAD3 and SP1 via concomitant binding to SMAD3/SP1 cis-regulatory elements within the MCEMP1 promoter. We also found that MCEMP1 regulates TGFβ-mediated monocyte chemotaxis, adhesion, and migration. Our results suggest that MCEMP1 may regulate the migration and transition of monocytes to monocyte-derived alveolar macrophages during pulmonary fibrosis development and progression.

PMID:38189137 | DOI:10.1152/ajpcell.00563.2023

J Nutr Biochem. 2024 Jan 5:109558. doi: 10.1016/j.jnutbio.2023.109558. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. Up to now, no treatment can stop the progression of IPF. Vitamin D3 (VD) reduces experimental lung fibrosis in murine models and depletion of vitamin D3 might be associated with the reduced survival of patients with IPF. In this context, we determined if VD can prevent the pro-fibrotic functions of human lung fibroblasts (HLFs) isolated from patients with IPF. IPF and control HLFs were derived from surgical lung biopsies collected from patients with IPF or with primary lung cancer, respectively. VD (3-100 nM) markedly reduced the basal and PDGF-induced proliferation of HLFs. VD also altered cell cycle by increasing the percentage of IPF HLFs arrested in the G0/G1 phase, and by downregulating the expression of various cell cycle regulatory proteins. In addition, VD barely prevented the TGF-β1-induced differentiation in HLFs. At 100 nM, VD slightly reduced the expression of the pro-fibrotic marker α-smooth muscle actin, and had no effect on fibronectin and collagen-1 expression. In contrast, 100 nM VD strongly inhibited the aerobic glycolytic metabolism induced by TGF- β1. Finally, VD reduced both the secretion of lactate, the levels of lactate deshydrogenase mRNA and the activity of intracellular LDH in IPF HLFs. In conclusion, our study shows that VD reduced pro-fibrotic functions of HLFs. These findings suggest that it might be interesting to assess the potential clinical benefits of vitamin D supplementation in patients with IPF, especially on lung function decline.

PMID:38185349 | DOI:10.1016/j.jnutbio.2023.109558

Commun Biol. 2024 Jan 6;7(1):52. doi: 10.1038/s42003-023-05739-5.

ABSTRACT

Patients with idiopathic pulmonary fibrosis show a strongly upregulated expression of chemokine CXCL14, whose target is still unknown. Screening of CXCL14 in a panel of human G protein-coupled receptors (GPCRs) revealed its potent and selective activation of the orphan MAS-related GPCR X2 (MRGPRX2). This receptor is expressed on mast cells and - like CXCL14 - upregulated in bronchial inflammation. CXCL14 induces robust activation of MRGPRX2 and its putative mouse ortholog MRGPRB2 in G protein-dependent and β-arrestin recruitment assays that is blocked by a selective MRGPRX2/B2 antagonist. Truncation combined with mutagenesis and computational studies identified the pharmacophoric sequence of CXCL14 and its presumed interaction with the receptor. Intriguingly, C-terminal domain sequences of CXCL14 consisting of 4 to 11 amino acids display similar or increased potency and efficacy compared to the full CXCL14 sequence (77 amino acids). These results provide a rational basis for the future development of potential idiopathic pulmonary fibrosis therapies.

PMID:38184723 | DOI:10.1038/s42003-023-05739-5

BMC Pulm Med. 2024 Jan 5;24(1):16. doi: 10.1186/s12890-023-02833-6.

ABSTRACT

BACKGROUND: The ILD-GAP scoring system is known to be useful in predicting prognosis in patients with interstitial lung disease (ILD). An elevated monocyte count was associated with increased risks of IPF poor prognosis. We examined whether the ILD-GAP scoring system combined with the monocyte ratio (ILD-GAPM) is superior to the conventional ILD-GAP model in predicting ILD prognosis.

METHODS: In patients with ILD treated between April 2013 and April 2017, we were retrospectively assessed the relationships between baseline clinical parameters, including age, sex, Charlson Comorbidity Index score (CCIS), ILD diagnosis, blood biomarkers, pulmonary function test results, and disease outcomes. In ILD patients were included idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), collagen vascular disease-related interstitial pneumonia (CVD-IP), chronic hypersensitivity pneumonitis (CHP), and unclassifiable ILD (UC-ILD). We also assessed the ability to predict prognosis was compared between the ILD-GAP and ILD-GAPM models.

RESULTS: A total of 179 patients (mean age, 73 years) were assessed. All of them were taken pulmonary function test, including percentage predicted diffusion capacity for carbon monoxide. ILD patients included 56 IPF cases, 112 iNSIP and CVD-IP cases, 6 CHP cases and 5 UC-ILD cases. ILD-GAPM provided a greater area under the receiver-operating characteristic curve (0.747) than ILD-GAP (0.710) for predicting 3-year ILD-related events. Furthermore, the log-rank test showed that the Kaplan-Meier curves in ILD-GAPM were significantly different by stage (P = 0.015), but not by stage in ILD-GAP (P = 0.074).

CONCLUSIONS: The ILD-GAPM model may be a more accurate predictor of prognosis for ILD patients than the ILD-GAP model.

PMID:38183005 | DOI:10.1186/s12890-023-02833-6

NPJ Regen Med. 2024 Jan 5;9(1):2. doi: 10.1038/s41536-023-00344-w.

ABSTRACT

Maintenance of the cellular boundary between airway and alveolar compartments during homeostasis and after injury is essential to prohibit pathological plasticity which can reduce respiratory function. Lung injury and disease can induce either functional alveolar epithelial regeneration or dysplastic formation of keratinized epithelium which does not efficiently contribute to gas exchange. Here we show that Sox2 preserves airway cell identity and prevents fate changes into either functional alveolar tissue or pathological keratinization following lung injury. Loss of Sox2 in airway epithelium leads to a loss of airway epithelial identity with a commensurate gain in alveolar and basal cell identity, in part due to activation of Wnt signaling in secretory cells and increased Trp63 expression in intrapulmonary basal-like progenitors. In idiopathic pulmonary fibrosis, loss of SOX2 expression correlates with increased WNT signaling activity in dysplastic keratinized epithelium. SOX2-deficient dysplastic epithelial cells are also observed in COVID-19 damaged lungs. Thus, Sox2 provides a molecular barrier that suppresses airway epithelial plasticity to prevent acquisition of alveolar or basal cell identity after injury and help guide proper epithelial fate and regeneration.

PMID:38182591 | DOI:10.1038/s41536-023-00344-w

Respir Med Case Rep. 2023 Dec 9;46:101960. doi: 10.1016/j.rmcr.2023.101960. eCollection 2023.

ABSTRACT

An 82-year-old man diagnosed with interstitial lung disease through computed tomography (CT) 1 year prior received a bivalent (tozinameran and famtozinameran) mRNA COVID-19 vaccine. He developed respiratory symptoms 1.5 months later, and chest high-resolution CT revealed new ground-glass opacities showing traction bronchiectasis. Transbronchial lung cryobiopsy revealed organizing acute lung injury and fibrosis with architectural destruction. The patient was diagnosed with an acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). The bivalent mRNA COVID-19 vaccination was determined as the cause of the AE-IPF based on detailed medical history and examination findings. High-dose corticosteroid therapy improved the patient's symptoms and radiological findings.

PMID:38178926 | PMC:PMC10765099 | DOI:10.1016/j.rmcr.2023.101960

Immunology. 2024 Jan 4. doi: 10.1111/imm.13748. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder involving scarring of pulmonary tissue and a subsequent decrease in respiratory capacity, ultimately resulting in death. Tartrate resistant acid phosphatase 5 (ACP5) plays a role in IPF but the exact mechanisms are yet to be elucidated. In this study, we have utilized various perturbations of the bleomycin mouse model of IPF including genetic knockout, RANKL inhibition, and macrophage adoptive transfer to further understand ACP5's role in pulmonary fibrosis. Genetic ablation of Acp5 decreased immune cell recruitment to the lungs and reduced the levels of hydroxyproline (reflecting extracellular matrix-production) as well as histological damage. Additionally, gene expression profiling of murine lung tissue revealed downregulation of genes including Ccl13, Mmp13, and Il-1α that encodes proteins specifically related to immune cell recruitment and macrophage/fibroblast interactions. Furthermore, antibody-based neutralization of RANKL, an important inducer of Acp5 expression, reduced immune cell recruitment but did not decrease fibrotic lung development. Adoptive transfer of Acp5-/- bone marrow-derived monocyte (BMDM) macrophages 7 or 14 days after bleomycin administration resulted in reductions of cytokine production and decreased levels of lung damage, compared to adoptive transfer of WT control macrophages. Taken together, the data presented in this study suggest that macrophage derived ACP5 plays an important role in development of pulmonary fibrosis and could present a tractable target for therapeutic intervention in IPF.

PMID:38178705 | DOI:10.1111/imm.13748

Respir Res. 2024 Jan 4;25(1):5. doi: 10.1186/s12931-023-02588-y.

ABSTRACT

BACKGROUND: Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with more than 200 entities and relevant differences in disease course and prognosis. Little data is available on hospitalisation patterns in ILD.

METHODS: The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for hospitalisations. Reasons for hospitalisation were classified as all cause, ILD-related and respiratory hospitalisations, and patients were analysed for frequency of hospitalisations, time to first non-elective hospitalisation, mortality and progression-free survival. Additionally, the risk for hospitalisation according to GAP index and ILD subtype was calculated by Cox proportional-hazard models as well as influencing factors on prediction of hospitalisation by logistic regression with forward selection.

RESULTS: In total, 601 patients were included. 1210 hospitalisations were recorded during the 6 months prior to registry inclusion until the last study visit. 800 (66.1%) were ILD-related, 59.3% of admissions were registered in the first year after inclusion. Mortality was associated with all cause, ILD-related and respiratory-related hospitalisation. Risk factors for hospitalisation were advanced disease (GAP Index stages II and III) and CTD (connective tissue disease)-ILDs. All cause hospitalisations were associated with pulmonary hypertension (OR 2.53, p = 0.005). ILD-related hospitalisations were associated with unclassifiable ILD and concomitant emphysema (OR = 2.133, p = 0.001) as well as with other granulomatous ILDs and a positive smoking status (OR = 3.082, p = 0.005).

CONCLUSION: Our results represent a crucial contribution in understanding predisposing factors for hospitalisation in ILD and its major impact on mortality. Further studies to characterize the most vulnerable patient group as well as approaches to prevent hospitalisations are warranted.

PMID:38178212 | PMC:PMC10765927 | DOI:10.1186/s12931-023-02588-y

Eur Respir J. 2024 Jan 4;63(1):2301954. doi: 10.1183/13993003.01954-2023. Print 2024 Jan.

NO ABSTRACT

PMID:38176704 | DOI:10.1183/13993003.01954-2023

Respir Med. 2024 Jan 2:107526. doi: 10.1016/j.rmed.2023.107526. Online ahead of print.

ABSTRACT

Patients with idiopathic fibrosing interstitial pneumonias (f-IIPs) mainly suffer from dyspnea. Refractory dyspnea, defined as persistent dyspnea despite optimal treatment, could be the signal to prescribe dyspnea relievers. We aimed to examine the prevalence and characteristics of refractory dyspnea in consecutive patients with f-IIPs. Refractory dyspnea was defined by an mMRC≥3 and also by a VAS dyspnea score≥2 at rest; the sensory and affective characteristics of refractory dyspnea (mMRC≥3) and associated quality of life (QoL) anxiety and depression were compared with non-refractory dyspnea (mMRC1-2) using the Multidimensional Dyspnea Profile (MDP), King's Brief Interstitial Lung Disease (KBILD) and Hospital Anxiety and Depression scale (HADs). We included 40 patients (24 men), aged 72 [68-79], FVC of 71 % [59-86] and DLCO 47 % [40-49]. Refractory dyspnea, was found in 38 % (95%CI:23-54) when defined by mMRC≥3 and in 67 % (95%CI:50-81) using a resting VAS dyspnea score ≥2. The agreement between the two definitions was low. Patients with refractory dyspnea (mMRC≥3) were more often women (60 % vs.28 %,p = 0.046), had a lower DLCO (24 % [22-43] vs.47 % [43-51],p = 0.014) and more frequently used oxygen (60 % vs.12 %,p = 0.003); they experience more intense air hunger (5/10 [(Johnson et al., 2017; Raghu et al., 2022; Banzett et al., 2015; Patel et al., 2012) 3-63-6 vs.2/10 [0-5],p = 0.018)). No significant differences were observed in VAS, MDP, KBILD, or HADs scores between refractory and non-refractory dyspnea patients. Our results indicate a significant frequency of refractory dyspnea in patients with f-IIPs and an association with air hunger but no impact on the affective dimension of dyspnea, anxiety, depression and QoL, suggesting that the mMRC score might not accurately identify patients distressed by their breathlessness.

PMID:38176572 | DOI:10.1016/j.rmed.2023.107526

BMC Pulm Med. 2024 Jan 5;24(1):15. doi: 10.1186/s12890-023-02831-8.

ABSTRACT

BACKGROUND: IPF is a complex lung disease whose aetiology is not fully understood, but diet may have an impact on its development and progression. Therefore, we investigated the potential causal connection between dietary intake and IPF through TSMR to offer insights for early disease prevention recommendations.

METHODS: The study incorporated 29 dietary exposure factors, oily fish intake, bacon intake, processed meat intake, poultry intake, beef intake, pork intake, lamb/mutton intake, non-oily fish intake, fresh fruit intake, cooked vegetable intake, baked bean intake, fresh tomato intake, tinned tomato intake, salad/raw vegetable intake, Fresh fruit intake, coffee intake, tea intake, water intake, red wine intake, average weekly beer plus cider intake, alcoholic drinks per week, cereal intake, bread intake, whole-wheat intake, whole-wheat cereal intake, cheese intake, yogurt intake, salt added to food and whole egg intake. The study explored the causal link between diet and IPF using TSMR analysis, predominantly the IVW method, and performed sensitivity analyses to validate the results.

RESULT: The study revealed that consuming oily fish, yogurt, and dried fruits had a protective effect against IPF, whereas the consumption of alcoholic beverages and beef was linked to an increased risk of IPF.

CONCLUSION: In this MR study, it was discovered that the consumption of oily fish, yogurt, and dried fruits exhibited a protective effect against IPF, whereas the intake of alcoholic beverages and beef was associated with an elevated risk of IPF. These findings underscore the significance of making informed and timely dietary decisions in IPF prevention.

PMID:38178024 | DOI:10.1186/s12890-023-02831-8

EMBO J. 2024 Jan;43(1):61-86. doi: 10.1038/s44318-023-00003-2. Epub 2023 Dec 15.

ABSTRACT

Accumulation of DNA damage in the lung induces cellular senescence and promotes age-related diseases such as idiopathic pulmonary fibrosis (IPF). Hence, understanding the mechanistic regulation of DNA damage repair is important for anti-aging therapies and disease control. Here, we identified an m6A-independent role of the RNA-binding protein YTHDC1 in counteracting stress-induced pulmonary senescence and fibrosis. YTHDC1 is primarily expressed in pulmonary alveolar epithelial type 2 (AECII) cells and its AECII expression is significantly decreased in AECIIs during fibrosis. Exogenous overexpression of YTHDC1 alleviates pulmonary senescence and fibrosis independent of its m6A-binding ability, while YTHDC1 deletion enhances disease progression in mice. Mechanistically, YTHDC1 promotes the interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair. These findings reveal a noncanonical function of YTHDC1 in delaying cellular senescence, and suggest that enhancing YTHDC1 expression in the lung could be an effective treatment strategy for pulmonary fibrosis.

PMID:38177310 | DOI:10.1038/s44318-023-00003-2

Am J Respir Crit Care Med. 2024 Jan 4. doi: 10.1164/rccm.202312-2213SO. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF.

METHODS: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's "feels, functions, survives" criteria.

RESULTS: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures .

CONCLUSION: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

PMID:38174955 | DOI:10.1164/rccm.202312-2213SO

Pulm Circ. 2024 Jan 3;14(1):e12311. doi: 10.1002/pul2.12311. eCollection 2024 Jan.

ABSTRACT

Pulmonary vascular dysfunction in the absence of pulmonary hypertension (PH) has been observed in patients with idiopathic pulmonary fibrosis (IPF). We describe the prevalence and etiology of elevated pulmonary vascular resistance (PVR) without PH among patients with IPF. Hemodynamic, echocardiographic, and functional respiratory imaging (FRI) data was compared between patients with IPF without PH with normal (<3 wood units) and elevated PVR (≥3 wood units). Mortality between these two groups were compared to patients with IPF and PH. Of 205 patients with IPF, there were 146 patients without PH, of whom 114 (78.1%) had a normal PVR and 32 (21.9%) who had a high PVR. Functional testing and hemodynamics were similar in the two groups, except for the cardiac index which was significantly lower in patients with a high PVR (2.3 vs. 2.6 L/min/m2; p = 0.004). Echocardiographic comparison demonstrated a higher tricuspid regurgitant velocity in those with a high PVR (3.4 vs 3.0 m/s; p = 0.046). FRI revealed proportionately fewer large vessels as a proportion of the vasculature in the patients without PH and elevated PVRs. Among patients without PH, PVR was associated with increased mortality. In conclusion, patients with IPF without PH but a high PVR appear to be a distinct phenotype with a prognosis between those with and without PH, likely reflecting the continuum of vascular dysfunction. The basis for this unique hemodynamic profile could not be definitively discerned although FRI suggested an aberrant anatomical vascular response.

PMID:38174158 | PMC:PMC10762875 | DOI:10.1002/pul2.12311

Respirol Case Rep. 2024 Jan 3;12(1):e01271. doi: 10.1002/rcr2.1271. eCollection 2024 Jan.

ABSTRACT

Extrapleural air is a rare condition that may concurrently develop with pneumomediastinum and pneumothorax, especially in older patients with fragile connective tissues. Physicians should consider extrapleural air to prevent inadvertent harm. Coronal reconstruction computed tomography images help appreciate extrapleural air and recognize the track of extrapulmonary air.

PMID:38173867 | PMC:PMC10763515 | DOI:10.1002/rcr2.1271