Respir Res. 2024 Jul 31;25(1):293. doi: 10.1186/s12931-024-02922-y.

ABSTRACT

BACKGROUND AND OBJECTIVE: Pooled analyses of previous randomized controlled trials reported that antifibrotics improved survival in patients with idiopathic pulmonary fibrosis (IPF), but the results were only based on short-term outcome data from selected patients who met strict criteria. Observational studies/meta-analyses also suggested that antifibrotics improve survival, but these studies failed to control for immortal time bias that considerably exaggerates drug effects. Therefore, whether antifibrotics truly improve long-term survival in patients with IPF in the real world remains undetermined and requires external validity.

METHODS: We used data from the Japanese National Claims Database to estimate the intention-to-treat effect of antifibrotics on mortality. To address immortal time bias, we employed models treating antifibrotic initiation as a time-dependent covariate and target trial emulation (TTE), both incorporating new-user designs for antifibrotics and treating lung transplantation as a competing event.

RESULTS: Of 30,154 patients with IPF, 14,525 received antifibrotics. Multivariate Fine-Gray models with antifibrotic initiation as a time-dependent covariate revealed that compared with no treatment, nintedanib (adjusted hazard ratio [aHR], 0.85; 95% confidence interval [CI], 0.81-0.89) and pirfenidone (aHR, 0.89; 95% CI, 0.86-0.93) were associated with reduced mortality. The TTE model also replicated the associations of nintedanib (aHR, 0.69; 95% CI, 0.65-0.74) and pirfenidone (aHR, 0.81; 95% CI, 0.78-0.85) with reduced mortality. Subgroup analyses confirmed this association regardless of age, sex, and comorbidities, excluding certain subpopulations.

CONCLUSIONS: The results of this large-scale real-world analysis support the generalizability of the association between antifibrotics and improved survival in various IPF populations.

PMID:39085869 | DOI:10.1186/s12931-024-02922-y

BMC Pulm Med. 2024 Jul 31;24(1):373. doi: 10.1186/s12890-024-03188-2.

ABSTRACT

BACKGROUND: The six-minute walk test (6MWT) is widely used to assess functional capacity and prognosis in patients with idiopathic pulmonary fibrosis (IPF). However, studies on oxygen saturation recovery after the 6MWT in patients with IPF are rare. In our study, we investigated the relationship between oxygen saturation recovery time and dyspnea, fatigue, quality of life, prognostic markers and pulmonary hypertension (PH).

METHODS: In this cross-sectional study, IPF patients diagnosed according to current guidelines and followed up in our Interstitial Lung Disease Outpatient Clinic between 2021 and 2022 were included. Demographics, data from spirometry, diffusion capacity measurement, arterial blood gas analysis, transthoracic echocardiography and the 6MWT were recorded. The oxygen saturation recovery time, distance saturation product (DSP), gender-age-physiology (GAP) index and composite physiological index (CPI) scores were calculated. Dyspnea severity was assessed by the modified Medical Research Council (mMRC) and Dyspnoea-12 (D-12) scales, fatigue severity by the Multidimensional Fatigue Inventory (MFI-20) and quality of life by the St George's Respiratory Questionnaire (SGRQ).

RESULTS: Fifty IPF patients (34 men, 16 women, age: 66.8 ± 7.3 years) were included in the study. The mean FVC was 77.8 ± 19.3%, the DLCO was 52.9 ± 17.1%, the 6-minute walk distance (6MWD) was 385.7 ± 90.6 m, the GAP index was 3.5 ± 1.5, and the CPI was 43.7 ± 14.1. Oxygen saturation after the 6MWT reached pretest values at an average of 135.6 ± 73.5 s. The oxygen saturation recovery time was longer in patients with higher GAP index scores (Rs = 0.870, p < 0.001), CPI scores (Rs = 0.906, p < 0.001), desaturation (Rs = 0.801, p < 0.001), FVC%/DLCO% (Rs = 0.432, p = 0.002), sPAP (Rs = 0.492, p = 0.001), TRV (Rs = 0.504, p = 0.001), mMRC (Rs = 0.913, p < 0.001), MFI-20 (Rs = 0.944, p < 0.001), D-12 scale (Rs = 0.915, p < 0.001) and SGRQ scores (Rs = 0.927, p < 0.001); lower FVC (%) (Rs=-0.627, p < 0.001), DLCO (%) (Rs=-0.892, p < 0.001), PaO2 (Rs=-0.779, p < 0.001), DSP (Rs=-0.835, p < 0.001), and 6MWD (Rs=-0.763, p < 0.001). A total of twenty patients (40%) exhibited an increased risk of PH. According to our multiple regression analysis, oxygen saturation recovery time was independently associated with the GAP index (p = 0.036), the lowest oxygen saturation occurring during the 6MWT (p = 0.011) and the SGRQ score (p < 0.001).

CONCLUSIONS: Our results showed that oxygen saturation recovery time is associated with dyspnea, fatigue, quality of life, increased risk of PH and prognostic markers in IPF. Therefore, we recommend continuous measurement of oxygen saturation after 6MWT until pretest values are reached.

PMID:39085811 | DOI:10.1186/s12890-024-03188-2

BMC Pulm Med. 2024 Jul 30;24(1):367. doi: 10.1186/s12890-024-03092-9.

ABSTRACT

PURPOSE: The extent of honeycombing and reticulation predict the clinical prognosis of IPF. Emphysema, consolidation, and ground glass opacity are visible in HRCT scans. To date, there have been few comprehensive studies that have used these parameters. We conducted automated quantitative analysis to identify predictive parameters for clinical outcomes and then grouped the subjects accordingly.

METHODS: CT images were obtained while patients held their breath at full inspiration. Parameters were analyzed using an automated lung texture quantification system. Cluster analysis was conducted on 159 IPF patients and clinical profiles were compared between clusters in terms of survival.

RESULTS: Kaplan-Meier analysis revealed that survival rates declined as fibrosis, reticulation, honeycombing, consolidation, and emphysema scores increased. Cox regression analysis revealed that reticulation had the most significant impact on survival rate, followed by honeycombing, consolidation, and emphysema scores. Hierarchical and K-means cluster analyses revealed 3 clusters. Cluster 1 (n = 126) with the lowest values for all parameters had the longest survival duration, and relatively-well preserved FVC and DLCO. Cluster 2 (n = 15) with high reticulation and consolidation scores had the lowest FVC and DLCO values with a predominance of female, while cluster 3 (n = 18) with high honeycombing and emphysema scores predominantly consisted of male smokers. Kaplan-Meier analysis revealed that cluster 2 had the lowest survival rate, followed by cluster 3 and cluster 1.

CONCLUSION: Automated quantitative CT analysis provides valuable information for predicting clinical outcomes, and clustering based on these parameters may help identify the high-risk group for management.

PMID:39080584 | DOI:10.1186/s12890-024-03092-9

BMC Pulm Med. 2024 Jul 31;24(1):370. doi: 10.1186/s12890-024-03186-4.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal progressive lung disease entailing significant impairment in health-related quality of life (HRQoL) and high socioeconomic burden. The course of IPF includes episodes of acute exacerbations (AE-IPF) leading to poor outcomes. This study aimed to compare management, costs and HRQoL of patients with AE-IPF to patients without AE-IPF during one year in Spain.

MATERIALS AND METHODS: In a 12-month, prospective, observational, multicenter study of IPF patients, healthcare resource use was recorded and costs related to AE-IPF were estimated and compared between patients with and without AE-IPF. HRQoL was measured with the St. George's Respiratory Questionnaire (SGRQ), EuroQoL 5 dimensions 5 levels questionnaire (EQ-5D-5L), EQ-5D visual analogue scale (EQ-VAS) and the Barthel Index.

RESULTS: 204 IPF patients were included: 22 (10.8%) experienced ≥ 1 acute exacerbation, and 182 (89.2%) did not. Patients with exacerbations required more primary care visits, nursing home visits, emergency visits, hospital admissions, pharmacological treatments and transport use (p < 0.05 for all comparisons). Likewise, patients with exacerbations showed higher annual direct health AE-IPF-related costs. In particular, specialized visits, emergency visits, days of hospitalization, tests, palliative care, transport in ambulance and economic aid (p < 0.05 for all comparisons). Exploratory results showed that patients with AE-IPF reported a non-significant but substantial decline of HRQoL compared with patients without AE-IPF, although causality can be inferred.

CONCLUSION: We observed significantly higher resource use and cost consumption and lower HRQoL among patients suffering exacerbations during the study. Thus, preventing or avoiding AE-IPF is key in IPF management.

PMID:39080648 | DOI:10.1186/s12890-024-03186-4

QJM. 2024 Jul 30:hcae147. doi: 10.1093/qjmed/hcae147. Online ahead of print.

ABSTRACT

BACKGROUND: The prognosis of idiopathic pulmonary fibrosis (IPF) patients is highly heterogeneous. Abnormalities in lipids and their metabolism play an important role in the development of IPF.

AIM: To investigate the value of lipid parameters, C-reactive protein (CRP), and high-density lipoprotein cholesterol/C-reactive protein (HDL-C/CRP) ratio levels in the prognosis of IPF patients.

DESIGN: An observational cohort study.

METHODS: We collected baseline data of non-IPF controls and IPF patients, and IPF patients were followed up for 4 years. All-cause death or lung transplantation and IPF-related death were the outcome events. Receiver operating characteristic (ROC) curves and Cox proportional hazards models were used to analyze the predictive effect of lipid parameters, CRP and HDL-C/CRP ratio on the prognosis of IPF patients.

RESULTS: IPF patients had lower HDL-C, HDL-C/CRP ratio and higher CRP compared to non-IPF controls. IPF patients who died or underwent lung transplantation were older and had worse pulmonary function, lower HDL-C, HDL-C/CRP ratio and higher CRP compared with surviving patients. HDL-C/CRP ratio was better than HDL-C and CRP in predicting all-cause death or lung transplantation. IPF patients with low HDL-C/CRP ratio had shorter survival times. HDL-C/CRP ratio and DLCO% of predicted were independent protective factors for all-cause death or lung transplantation and IPF-related death in IPF patients, while age and GAP stage ≥ 2 (HR = 4.927)were independent risk factors for all-cause death or lung transplantation. Age > 65 years (HR = 3.533) was an independent risk factor for IPF-related death.

CONCLUSIONS: HDL-C/CRP ratio was a valid predictor of clinical outcomes in IPF patients, including all-cause death or lung transplantation and IPF-related death.

PMID:39078215 | DOI:10.1093/qjmed/hcae147

Am J Respir Crit Care Med. 2024 Jul 30. doi: 10.1164/rccm.202407-1290ED. Online ahead of print.

NO ABSTRACT

PMID:39078175 | DOI:10.1164/rccm.202407-1290ED

Am J Respir Crit Care Med. 2024 Jul 30. doi: 10.1164/rccm.202406-1194ED. Online ahead of print.

NO ABSTRACT

PMID:39078173 | DOI:10.1164/rccm.202406-1194ED

Cureus. 2024 Jun 29;16(6):e63467. doi: 10.7759/cureus.63467. eCollection 2024 Jun.

ABSTRACT

A 72-year-old man with idiopathic pulmonary fibrosis (IPF) was on home oxygen therapy at 1 L/min. He fell approximately 3 m onto a concrete surface while painting the roof of his home and was emergently transported to a local hospital due to pain in his lower back and right lower limb. His initial Krebs von den Lungen level decreased with medical treatments but has shown an increasing trend over the past three respiratory outpatient visits. His other medical conditions, including dyslipidemia, lumbar pain, and allergic rhinitis, were treated with several drugs prescribed by a nearby clinic. At the previous hospital, an increased oxygen demand of around 5 L via mask was noted, although other vital signs were stable. A plain whole-body computed tomography (CT) scan revealed pulmonary edema, a fracture of the right femoral neck, and a fracture of the third lumbar vertebral body. During transfer to our hospital for surgery, crossing the Amagi Pass at an elevation of approximately 830 m, the patient's respiratory condition rapidly deteriorated. Upon arrival, the cardiac wall movement was hyperdynamic, and PaO2 was 29 mmHg under supplemental oxygen at 15 L/min, necessitating oral endotracheal intubation and initiation of mechanical ventilation. A chest CT scan showed worsening diffuse ground-glass opacities in both lungs compared to the previous CT scan at the referring hospital. Despite positive pressure ventilation with the mechanical ventilator, the patient's condition did not improve, and he died in the emergency room. Acute respiratory distress syndrome (ARDS) can occur following severe trauma but the onset of ARDS due to moderate trauma is extremely rare. Considering the possibility of an acute exacerbation of IPF prior to the injury, this report discusses the possibility of developing ARDS due to trauma-induced cytokines and lung damage from damage-associated molecular patterns, the possibility of inhaling dust while working on the roof, pneumonia caused by prescribed medication, viral infections, exposure to pollen and/or high altitude while passing through the mountain pass, and hypoxemia-inducing pulmonary edema.

PMID:39077261 | PMC:PMC11285813 | DOI:10.7759/cureus.63467

Res Diagn Interv Imaging. 2022 Oct 29;4:100017. doi: 10.1016/j.redii.2022.100017. eCollection 2022 Dec.

ABSTRACT

OBJECTIVES: To develop an imaging prognostic model for idiopathic pulmonary fibrosis (IPF) patients using hybrid auto-segmentation radiomics analysis, and compare the predictive ability between the radiomics analysis and conventional visual score methods.

METHODS: Data from 72 IPF patients who had undergone CT were analyzed. In the radiomics analysis, quantitative CT analysis was performed using the semi-auto-segmentation method. In the visual method, the extent of radiologic abnormalities was evaluated and the overall percentage of lung involvement was calculated by averaging values for six lung zones. Using a training cohort of 50 cases, we generated a radiomics model and a visual score model. Subsequently, we investigated the predictive ability of these models in a testing cohort of 22 cases.

RESULTS: Three significant prognostic factors such as contrast, Idn, and cluster shade were selected by LASSO Cox regression analysis. In the visual method, multivariate Cox regression analysis revealed that honeycombing and reticulation were significant prognostic factors. Subsequently, a predictive nomogram for prognosis in IPF patients was established using these factors. In the testing cohort, the c-index of the visual and radiomics nomograms were 0.68 and 0.74, respectively. When dividing the cohort into high-risk and low-risk groups using the median nomogram score, significant differences in overall survival (OS) in the visual and radiomics models were observed (P=0.000 and P=0.0003, respectively).

CONCLUSIONS: The prediction model with hybrid radiomics analysis had a better ability to predict OS in IPF patients than that of the visual method.

PMID:39076611 | PMC:PMC11265392 | DOI:10.1016/j.redii.2022.100017

ERJ Open Res. 2024 Jul 29;10(4):00666-2023. doi: 10.1183/23120541.00666-2023. eCollection 2024 Jul.

ABSTRACT

BACKGROUND: The Gender, Age and Physiology (GAP) model is a simple mortality prediction tool in patients with idiopathic pulmonary fibrosis that uses demographic and physiological variables available at initial evaluation. White blood cell variables may have associations with idiopathic pulmonary fibrosis outcomes. We evaluated whether incorporating blood cell counts in modified GAP (cGAP) models would improve outcome prediction in patients with idiopathic pulmonary fibrosis.

PATIENTS AND METHODS: This retrospective analysis included pooled data from phase 3 randomised trials of pirfenidone in idiopathic pulmonary fibrosis (ASCEND, CAPACITY 004, CAPACITY 006). Study outcomes (disease progression, all-cause mortality, all-cause hospitalisation, respiratory-related hospitalisation) were evaluated during the initial 1-year period. Shared frailty models were used to evaluate associations between continuous and categorical baseline white and red blood cell parameters and study outcomes in a bivariate context, and to evaluate the impact of adding continuous monocyte count (cGAP1) or white and red blood cell parameters (cGAP2) to traditional GAP variables in a multivariable context based on C-statistics changes.

RESULTS: Data were pooled from 1247 patients (pirfenidone, n=623; placebo, n=624). Significant associations (bivariate analyses) were idiopathic pulmonary fibrosis progression with neutrophil and eosinophil counts; all-cause mortality with monocyte and neutrophil counts; all-cause hospitalisation with monocyte count, neutrophil count and haemoglobin level; and respiratory-related hospitalisation with monocyte count, neutrophil count and haemoglobin level. In multivariate analyses, C-statistics were highest for the cGAP2 model for each of the outcomes.

CONCLUSION: Modified GAP models incorporating monocyte counts alone or plus other white and red blood cell variables may be useful to improve prediction of outcomes in patients with idiopathic pulmonary fibrosis.

PMID:39076530 | PMC:PMC11284599 | DOI:10.1183/23120541.00666-2023

Respir Med. 2024 Jul 27:107748. doi: 10.1016/j.rmed.2024.107748. Online ahead of print.

ABSTRACT

BACKGROUND: In patients with interstitial lung disease (ILD), exercise-induced desaturation during the six-minute walk test (6MWT), specifically nadir oxygen saturation (nSpO2) of ≤88% is a negative prognostic marker. As the 6MWT is often impractical for ILD patients, the aim of this study is to compare the 1-minute sit-to-stand test (1minSTS) with the 6MWT to detect exercise-induced desaturation.

METHODS: Participants were recruited from a tertiary referral clinic with both tests performed on the same day. Utilising Bland-Altman analysis, the relationship between nSpO2 on 1minSTS and 6MWT was determined. An area under the receiver operating characteristic curve (AUC) determined the ability of nSpO2 on 1minSTS test to predict SpO2 ≤88% on 6MWT.

RESULTS: Fifty participants completed the study (idiopathic pulmonary fibrosis n=24,48%; connective tissue disease associated ILD n=20,40%; other ILD n=6,12%). Mean (SD) FVC%pred was 73±16%, mean DLCO%pred 57±16% and resting SpO2 99±1%. The 1minSTS resulted in less exercise-induced oxygen desaturation, with a median IQR nSpO2 of 95% (89-98) and 93% (85-96) respectively (p<0.001). Moderate agreement was determined between the nSpO2 on both tests, with a mean difference of 3.2% [-14 to +3.0%]. The 1minSTS test accurately identified participants with nSpO2 ≤88% on 6MWT (AUC 0.96). Oxygen desaturation ≤ 94% during the 1minSTS test provided 100% sensitivity and 87% specificity for oxygen desaturation ≤88% at 6MWT.

CONCLUSION: This study demonstrates that exercise-induced oxygen desaturation during the 1minSTS test correlates with oxygen desaturation on 6MWT. The 1minSTS may be a practical screening tool for ILD patients who would benefit from further exercise testing.

PMID:39074595 | DOI:10.1016/j.rmed.2024.107748

Pulm Ther. 2024 Jul 29. doi: 10.1007/s41030-024-00267-x. Online ahead of print.

ABSTRACT

INTRODUCTION: Clinical practice guidelines recommend autoimmune serological testing in patients newly diagnosed with interstitial lung disease of apparently unknown cause who may have idiopathic pulmonary fibrosis (IPF), in order to exclude connective tissue disease (CTD). Autoantibody positivity has been associated with unique patient profiles and prognosis in patients with IPF who otherwise lack a CTD diagnosis.

METHODS: This post-hoc analysis of patients with IPF from the Phase III ASCEND trial (NCT01366209) evaluated the association of antinuclear antibodies (ANA), rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) status with baseline disease characteristics, disease progression [percent predicted forced vital capacity (%FVC), forced vital capacity (FVC) volume and progression-free survival (PFS)], and treatment outcomes with pirfenidone and placebo (%FVC, FVC and PFS).

RESULTS: Of 555 participants, 244/514 (47.5%) were ANA positive (ANA+), 83/514 (16.1%) had high ANA+ (ANA titre ≥ 1:160 or positive nucleolar- or centromere-staining patterns), 60/555 (10.8%) were RF positive (RF+) and/or anti-CCP positive (anti-CCP+) and 270/514 (52.5%) were autoantibody negative (AAb-). Baseline demographics and characteristics were generally comparable between autoantibody subgroups. Although not statistically significant, more placebo-treated participants with ANA+ or high ANA+ had a decline from baseline to Week 52 of ≥ 10% in %FVC or death (48.7% and 55.9%, respectively) or in FVC volume or death (48.7% and 47.1%, respectively) compared with the AAb- group (%FVC or death: 42.0%; FVC volume or death: 42.0%). The RF+ and/or anti-CCP+ group was similar to AAb-. No differences were observed in PFS. A treatment benefit for pirfenidone versus placebo was observed regardless of autoantibody status [PFS: ANA+ HR (95% CI): 0.56 (0.37 to 0.86), P = 0.007; AAb- HR (95% CI): 0.50 (0.32 to 0.78), P = 0.002].

CONCLUSION: IPF disease course did not differ by autoantibody status in ASCEND. Pirfenidone had a treatment benefit regardless of the presence of ANA.

TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01366209.

PMID:39073523 | DOI:10.1007/s41030-024-00267-x

Chem Biodivers. 2024 Jul 29:e202401030. doi: 10.1002/cbdv.202401030. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial disease leading to pulmonary damage and respiratory failure. We aimed to investigate the effect of prickly pear molasses (PPM) on an experimental model of pulmonary fibrosis induced by bleomycin (BLM) in Wistar rat. Animals were divided into 5 groups: the control group (G1), the BLM group (G2) and three groups (G3, G4, G5) receiving a single intra-tracheal injection of BLM (4 mg/kg) and PPM (at 2, 4.5 and10 %) that was introduced into the diet one week before BLM injection and continued for 3 weeks. Our phytochemical results revealed significant polyphenol and flavonoid content. LCMS analysis revealed the presence of Sinapinic acid, t-ferulic acid, t-cinnamic acid, Caffeic acid, gallic acid and vallinic acid among others. Our histological study revealed significant decrease in collagen deposition in the groups of rats treated with 4.5% and 10% molasses compared to BLM group. Oxidative stress in pulmonary tissues was investigated using catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) assays. Treatment with PPM normalized the disturbance in the level of these oxidative markers in G3,G4, G5 compared to G2. In conclusion, PPM exhibit antifibrotic and antioxidant activities in BLM model of lung fibrosis.

PMID:39073317 | DOI:10.1002/cbdv.202401030

Tissue Barriers. 2024 Jul 29:2386183. doi: 10.1080/21688370.2024.2386183. Online ahead of print.

ABSTRACT

Diabetes Mellitus presents a formidable challenge as one of the most prevalent and complex chronic diseases, exerting significant strain on both patients and the world economy. It is recognized as a common comorbidity among severely ill individuals, often leading to a myriad of micro- and macro-vascular complications. Despite extensive research dissecting the pathophysiology and molecular mechanisms underlying vascular complications of diabetes, relatively little attention has been paid to potential lung-related complications. This review aims to illuminate the impact of diabetes on prevalent respiratory diseases, including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), tuberculosis (TB), pneumonia infections, and asthma, and compare the vascular complications with other vascular beds. Additionally, we explore the primary mechanistic pathways contributing to these complications, such as the expression modulation of blood-tissue-barrier proteins, resulting in increased paracellular and transcellular permeability, and compromised immune responses rendering diabetes patients more susceptible to infections. The activation of inflammatory pathways leading to cellular injury and hastening the onset of these respiratory complications is also discussed.

PMID:39072526 | DOI:10.1080/21688370.2024.2386183

bioRxiv [Preprint]. 2024 Jul 19:2024.07.17.603936. doi: 10.1101/2024.07.17.603936.

ABSTRACT

Immune-mediated diseases are characterized by aberrant immune responses, posing significant challenges to global health. In both inflammatory and autoimmune diseases, dysregulated immune reactions mediated by tissue-residing immune and non-immune cells precipitate chronic inflammation and tissue damage that is amplified by peripheral immune cell extravasation into the tissue. Chemokine receptors are pivotal in orchestrating immune cell migration, yet deciphering the signaling code across cell types, diseases and tissues remains an open challenge. To delineate disease-specific cell-cell communications involved in immune cell migration, we conducted a meta-analysis of publicly available single-cell RNA sequencing (scRNA-seq) data across diverse immune diseases and tissues. Our comprehensive analysis spanned multiple immune disorders affecting major organs: atopic dermatitis and psoriasis (skin), chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (lung), ulcerative colitis (colon), IgA nephropathy and lupus nephritis (kidney). By interrogating ligand-receptor (L-R) interactions, alterations in cell proportions, and differential gene expression, we unveiled intricate disease- specific and common immune cell chemoattraction and extravasation patterns. Our findings delineate disease-specific L-R networks and shed light on shared immune responses across tissues and diseases. Insights gleaned from this analysis hold promise for the development of targeted therapeutics aimed at modulating immune cell migration to mitigate inflammation and tissue damage. This nuanced understanding of immune cell dynamics at the single-cell resolution opens avenues for precision medicine in immune disease management.

PMID:39071425 | PMC:PMC11275869 | DOI:10.1101/2024.07.17.603936

Eur J Pharmacol. 2024 Jul 26:176843. doi: 10.1016/j.ejphar.2024.176843. Online ahead of print.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a fatal progressive condition often requiring lung transplantation. Accelerated senescence of type II alveolar epithelial cells (AECII) plays a crucial role in pulmonary fibrosis progression through the secretion of the senescence-associated secretory phenotype (SASP). Low-dose carbon monoxide (CO) possesses anti-inflammatory, anti-oxidative, and anti-aging properties. This study aims to explore the preventive effects of CO-releasing molecule 2 (CORM2) in a bleomycin-induced pulmonary fibrosis model.

METHODS: We established an pulmonary fibrosis model in C57BL/6J mice and evaluated the impact of CORM2 on fibrosis pathology using Masson's trichrome staining, fluorescence staining, and pulmonary function tests. Fibrogenic marker expression and SASP secretion in tissues and AECII cells were analyzed using qRT-PCR, Western blot, and ELISA assays both in vivo and in vitro. Additionally, we investigated DNA damage and cellular senescence through immunofluorescence and SA-β-gal staining.

RESULTS: CORM2 showed a preventive effect on bleomycin-induced lung fibrosis by improving pulmonary function and reducing the expression of fibrosis-related genes, such as TGF-β, α-SMA, Collagen I/III. CORM2 decreased the DNA damage response by inhibiting γ-H2AX, p53, and p21. We identified PAI-1 as a new target gene that was downregulated by CORM2, and which was associated with cellular senescence and fibrosis. CORM2 effectively inhibited cellular senescence and delayed EMT occurrence in AECII cells.

CONCLUSION: Our study highlights the potential of CORM2 in preventing DNA damage-induced cellular senescence in bleomycin-induced pulmonary fibrosis through modulation of the p53/PAI-1 signaling pathway. These findings underscore the promising prospects of CORM2 in targeting cellular senescence and the p53/PAI-1 pathway as a potential preventive strategy for IPF.

PMID:39068977 | DOI:10.1016/j.ejphar.2024.176843

Drug Metab Pharmacokinet. 2024 Jun 10;57:101025. doi: 10.1016/j.dmpk.2024.101025. Online ahead of print.

ABSTRACT

Nintedanib is used to treat idiopathic pulmonary fibrosis, systemic sclerosis, interstitial lung disease, and progressive fibrotic interstitial lung disease. It is primarily cleared via hepatic metabolism, hydrolysis, and glucuronidation. In addition, formation of the iminium ion, a possible reactive metabolite, was predicted based on the chemical structure of nintedanib. To obtain a hint which may help to clarify the cause of nintedanib-induced liver injury, we investigated whether iminium ions were formed in the human liver. To detect unstable iminium ions using liquid chromatography-tandem mass spectrometry (LC-MS/MS), potassium cyanide was added to the reaction mixture as a trapping agent. Human liver and intestinal microsomes were incubated with nintedanib in the presence of NADPH to form two iminium ion metabolites on the piperazine ring. Their formation is strongly inhibited by ketoconazole, a potent cytochrome P450 (CYP) 3A4 inhibitor. Among the recombinant P450s, only CYP3A4 formed cyanide adducts. The role of CYP3A4 was supported by the positive correlation between CYP3A4 protein abundance, as determined by LC-MS-based proteomics, and the formation of cyanide adducts in 25 individual human liver microsomes. In conclusion, we have demonstrated that iminium ion metabolites are formed from nintedanib by CYP3A4 as potential reactive metabolites.

PMID:39068856 | DOI:10.1016/j.dmpk.2024.101025

Clin Exp Med. 2024 Jul 28;24(1):172. doi: 10.1007/s10238-024-01447-4.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a diagnosis of exclusion, requiring that potential etiologies of interstitial lung disease be ruled out. Antinuclear antibody (ANA) testing is commonly performed in individuals with IPF, but the clinical significance of ANA positivity remains uncertain. A retrospective search identified 161 patients diagnosed with IPF between May 2010 and January 2021. Data on ANA titers at the time of diagnosis were available in all cases. Mean age of the patients was 66.4 ± 9.6 years; 70.8% were male. ANA titers were high (≥ 1:160) in 25.4% of the cohort. Baseline characteristics were comparable between those with high and low ANA titers. During follow-up (median 28 months), 93 patients (57%) died. On Cox proportional-hazards analysis with lung transplantation entered as a competing risk and adjusting for potential confounders (age, sex, and baseline forced vital capacity and diffusing lung capacity for carbon monoxide), ANA ≥ 1:160, as a dichotomized variable, was significantly associated with case-specific mortality (HR 2.25, 95% CI 1.14-4.42, P = 0.02) and older age (for each 10-year increment, HR 1.55, 95% CI 1.07-2.25, P = 0.02). High ANA titers appear to be associated with increased mortality in IPF. This finding emphasizes the potential prognostic value of ANA testing. Further studies are needed to validate these findings and explore their implications for patient management.

PMID:39068615 | DOI:10.1007/s10238-024-01447-4

Hum Reprod Update. 2024 Jul 27:dmae023. doi: 10.1093/humupd/dmae023. Online ahead of print.

ABSTRACT

BACKGROUND: Fibrosis is an important pathological feature of endometriotic lesions of all subtypes. Fibrosis is present in and around endometriotic lesions, and a central role in its development is played by myofibroblasts, which are cells derived mainly after epithelial-to-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT). Transforming growth factor-β (TGF-β) has a key role in this myofibroblastic differentiation. Myofibroblasts deposit extracellular matrix (ECM) and have contracting abilities, leading to a stiff micro-environment. These aspects are hypothesized to be involved in the origin of endometriosis-associated pain. Additionally, similarities between endometriosis-related fibrosis and other fibrotic diseases, such as systemic sclerosis or lung fibrosis, indicate that targeting fibrosis could be a potential therapeutic strategy for non-hormonal therapy for endometriosis.

OBJECTIVE AND RATIONALE: This review aims to summarize the current knowledge and to highlight the knowledge gaps about the role of fibrosis in endometriosis. A comprehensive literature overview about the role of fibrosis in endometriosis can improve the efficiency of fibrosis-oriented research in endometriosis.

SEARCH METHODS: A systematic literature search was performed in three biomedical databases using search terms for 'endometriosis', 'fibrosis', 'myofibroblasts', 'collagen', and 'α-smooth muscle actin'. Original studies were included if they reported about fibrosis and endometriosis. Both preclinical in vitro and animal studies, as well as research concerning human subjects were included.

OUTCOMES: Our search yielded 3441 results, of which 142 studies were included in this review. Most studies scored a high to moderate risk of bias according to the bias assessment tools. The studies were divided in three categories: human observational studies, experimental studies with human-derived material, and animal studies. The observational studies showed details about the histologic appearance of fibrosis in endometriosis and the co-occurrence of nerves and immune cells in lesions. The in vitro studies identified several pro-fibrotic pathways in relation to endometriosis. The animal studies mainly assessed the effect of potential therapeutic strategies to halt or regress fibrosis, for example targeting platelets or mast cells.

WIDER IMPLICATIONS: This review shows the central role of fibrosis and its main cellular driver, the myofibroblast, in endometriosis. Platelets and TGF-β have a pivotal role in pro-fibrotic signaling. The presence of nerves and neuropeptides is closely associated with fibrosis in endometriotic lesions, and is likely a cause of endometriosis-associated pain. The process of fibrotic development after EMT and FMT shares characteristics with other fibrotic diseases, so exploring similarities in endometriosis with known processes in diseases like systemic sclerosis, idiopathic pulmonary fibrosis or liver cirrhosis is relevant and a promising direction to explore new treatment strategies. The close relationship with nerves appears rather unique for endometriosis-related fibrosis and is not observed in other fibrotic diseases.

REGISTRATION NUMBER: N/A.

PMID:39067455 | DOI:10.1093/humupd/dmae023

Int Immunopharmacol. 2024 Jul 26;139:112766. doi: 10.1016/j.intimp.2024.112766. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable lung disease characterized by unknown etiology. This study employs robust ranking aggregation to identify consistent differential genes across multiple datasets, aiming to enhance prognostic evaluation and facilitate the development of more effective immunotherapy strategies for IPF. Using the GSE10667, GSE110147, and GSE24206 datasets, the analysis identifies 92 robust differentially expressed genes (DEGs), including SPP1, IGF1, ASPN, and KLHL13, highlighted as potential biomarkers through machine learning and experimental validation. Additionally, significant differences in immune cell types between IPF samples and controls, such as Plasma cells, Macrophages M0, Mast cells resting, T cells CD8, and NK cells resting, inform the construction of diagnostic and survival prediction models, demonstrating good applicability. These findings provide insights into IPF pathophysiology and suggest potential therapeutic targets.

PMID:39067403 | DOI:10.1016/j.intimp.2024.112766