Ann Thorac Med. 2023 Oct-Dec;18(4):173-181. doi: 10.4103/atm.atm_7_23. Epub 2023 Oct 17.

ABSTRACT

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 rapidly spread across the globe causing over 6 million deaths and major compromization of health facilities. The vast majority of survivors post-COVID-19 are left with variable degrees of health sequelae including pulmonary, neurological, psychological, and cardiovascular complications. Post-COVID-19 pulmonary fibrosis is one of the major concerns arising after the recovery from this pandemic. Risk factors for post-COVID-19 pulmonary fibrosis include age, male sex, and the severity of COVID-19 disease. High-resolution computed tomography provides diagnostic utility to diagnose pulmonary fibrosis as it provides more details regarding the pattern and the extent of pulmonary fibrosis. Emerging data showing similarities between post-COVID-19 pulmonary fibrosis and idiopathic pulmonary fibrosis, finding that needs further exploration. The management of post-COVID-19 pulmonary fibrosis depends on many factors but largely relies on excluding other causes of pulmonary fibrosis, the extent of fibrosis, and physiological impairment. Treatment includes immunosuppressants versus antifibrotics or both.

PMID:38058790 | PMC:PMC10697304 | DOI:10.4103/atm.atm_7_23

Ann Thorac Med. 2023 Oct-Dec;18(4):217-218. doi: 10.4103/atm.atm_107_23. Epub 2023 Oct 17.

ABSTRACT

End-stage lung disease from nonrecovered COVID-19 acute respiratory distress syndrome has become an increasingly frequent indication for lung transplant. Although reports of lung transplant recipients (LTRs) with COVID-19 suggest an increased risk for hospitalization, respiratory failure, and death, little is known about retransplant for COVID-19-related lung graft failure. In this manuscript, we present a 49-year-old man who received bilateral lung retransplantation for COVID-19-related lung graft failure, 7½ years after his initial transplant for idiopathic pulmonary fibrosis. Our case suggests that retransplantation may be a viable option for critically ill LTRs with COVID-19-related graft failure, even in the presence of other organ dysfunction, provided that they are in good condition and have an immunologically favorable donor.

PMID:38058783 | PMC:PMC10697303 | DOI:10.4103/atm.atm_107_23

Curr Gastroenterol Rep. 2023 Dec 7. doi: 10.1007/s11894-023-00906-4. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: To discuss all the various motility disorders impacting people with Cystic Fibrosis (PwCF) and provide diagnostic and management approaches from a group of pediatric and adult CF and motility experts and physiologists with experience in the management of this disease.

RECENT FINDINGS: Gastrointestinal (GI) symptoms coexist with pulmonary symptoms in PwCF regardless of age and sex. The GI manifestations include gastroesophageal reflux disease, esophageal dysmotility gastroparesis, small bowel dysmotility, small intestinal bacterial overgrowth syndrome, distal idiopathic obstruction syndrome, constipation, and pelvic floor disorders. They are quite debilitating, limiting the patients' quality of life and affecting their nutrition and ability to socialize. This genetic disorder affects many organ systems and is chronic, potentially impacting fertility and future family planning, requiring a multidisciplinary approach. Our review discusses the treatments of motility disorders in CF, their prevalence and pathophysiology. We have provided a framework for clinicians who care for these patients that can help to guide their clinical management.

PMID:38057499 | DOI:10.1007/s11894-023-00906-4

Kyobu Geka. 2023 Sep;76(10):834-839.

ABSTRACT

This article describes the perioperative complications, perioperative risk assessment, and perioperative management of patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease, especially idiopathic pulmonary fibrosis( IPF), which are the leading diseases in respiratory dysfunction. In COPD, testing for forced expiratory volume during the first second and pulmonary diffusing capacity is important and an algorithm for testing has been presented by the Japanese Association for Chest Surgery. Acute exacerbation of IPF is the leading cause of postoperative mortality in Japan, and risk factors are being analyzed. To reduce the occurrence of postoperative complications, it is important to carry out a risk assessment, select appropriate surgical strategy, and implement a well-planned perioperative management.

PMID:38056846

Int Immunopharmacol. 2023 Dec 5;126:111316. doi: 10.1016/j.intimp.2023.111316. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a serious, lifelong lung disease with high morbidity and high mortality. Menstrual blood-derived stem cells (MenSCs) derived exosomes (MenSCs-Exo) emerge as an attractive tool for the treatment of acute lung injury and fibrosis-related diseases. However, more comprehensive mechanism over how MenSCs derived exosomes exhibits anti-pulmonary fibrosis needs to be elucidated. In this study, TGF-β was used to construct cell fibrosis model, and bleomycin (BLM) was applied to induce lung tissue fibrosis mice model. BLM- and TGF-β1-induced cellular reactive oxygen species (ROS), mitochondrial DNA (mtDNA) damage, and lung epithelial cell apoptosis were alleviated by MenSCs-Exo treatment in vivo and in vitro. Besides, it was found that MenSCs-Exo delivered miR-let-7 into MLE-12 cells/lung epithelial cell and the reduction of miR-let-7 blocked the improvement produced by MenSCs-Exo. Mechanistically, miR-let-7 directly bound to Sp3 and negatively regulated its expression. Sp3 elevation promoted the expression of ferroptosis-related protein and mitochondrial DNA (mtDNA) damage markers via recruiting HDAC2, thereby inactivating keap1/Nrf2 signal cascade, which were confirmed in BLM-induced pulmonary fibrosis mice model under the combination therapy of the MenSCs-Exo and let-7 inhibitor. Collectively, MenSCs derived exosomes could transmit miR-let-7 into MLE-12 cells to inhibit the expression of Sp3, thereby weakening the recruitment effect of Sp3 on HDAC2, lifting the deacetylation restriction of HDAC2 on Nrf2, and enhancing the Nrf2 pathway. These changes further declined ferroptosis and delayed the pathological process of oxidative damage and lung epithelial cell apoptosis in PF.

PMID:38056200 | DOI:10.1016/j.intimp.2023.111316

BMC Pulm Med. 2023 Dec 5;23(1):486. doi: 10.1186/s12890-023-02795-9.

ABSTRACT

BACKGROUND: The information needs of patients and their families regarding interstitial lung disease (ILD) have yet to be studied in detail, and few reports have examined the differences in information needs according to patient status. This study aimed to determine whether there are differences in information needs between outpatients with ILD and their family caregivers and whether these differences depend on long-term oxygen therapy use.

METHODS: Patients with fibrotic ILDs and their families who visited Kyoto University Hospital between February 2020 and March 2022 were recruited for this descriptive study. Fibrotic ILDs included idiopathic pulmonary fibrosis (IPF), other idiopathic interstitial pneumonias (IIPs) than IPF, connective tissue disease-associated ILD (CTD-ILD), and fibrotic hypersensitivity pneumonia. Data were obtained from electronic patient records and questionnaires. Descriptive data analyses were performed.

RESULTS: Sixty-five patients and their family caregivers were analyzed. Twenty-seven (41.5%) patients had IIPs (IPF 9 and other IIPs 18), 34 (52.3%) had CTD-ILD, and 4 (6.2%) had fibrotic hypersensitivity pneumonia. The most common relationship between the patient and their family was a spouse (67.7%), with 80% living together. The primary information needs among patients and their family caregivers were common up to the third rank but differed from the rest. Patients were interested in "when and where to contact health care providers" and "end-of-life care and advanced directives," while family caregivers were interested in "diet and nutrition" and "care and support at home." Patients with long-term oxygen therapy had higher needs for "end-of-life care and advanced directives" and "how to manage breathlessness, cough, and fatigue," while the needs for "drugs for ILD" and "acute exacerbation of ILD" were relatively low. Family caregivers were interested in "diet and nutrition" in the long-term oxygen therapy group and "acute exacerbation of ILD" in the no long-term oxygen therapy group.

CONCLUSIONS: This study found that the information needs of patients and their family caregivers were not the same and that the aspect of information needs differed by long-term oxygen therapy status. Healthcare providers should consider the position of the recipient of information, the appropriate time based on the patient's condition, and the necessary information.

PMID:38053142 | DOI:10.1186/s12890-023-02795-9

Respir Res. 2023 Dec 6;24(1):304. doi: 10.1186/s12931-023-02582-4.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with a poor prognosis. Current/available clinical prediction tools have limited sensitivity and accuracy when evaluating clinical outcomes of IPF. Research has shown that focal adhesion kinase (FAK), produced by the protein tyrosine kinase 2 (PTK2) gene, is crucial in IPF development. FAK activation is a characteristic of lesional fibroblasts; Thus, FAK may be a valuable therapeutic target or prognostic biomarker for IPF. This study aimed to create a gene signature based on PTK2-associated genes and microarray data from blood cells to predict disease prognosis in patients with IPF. PTK2 levels were found to be higher in lung tissues of IPF patients compared to healthy controls, and PTK2 inhibitor Defactinib was found to reduce TGFβ-induced FAK activation and increase α-smooth muscle actin. Although the blood PTK2 levels were higher in IPF patients, blood PTK level alone could not predict IPF prognosis. From 196 PTK2-associated genes, 11 genes were prioritized to create a gene signature (PTK2 molecular signature) and a risk score system using univariate and multivariate Cox regression analysis. Patients were divided into high-risk and low-risk groups using PTK2 molecular signature. Patients in the high-risk group experienced decreased survival rates compared to patients in the low-risk group across all discovery and validation cohorts. Further functional enrichment and immune cell proportion analyses revealed that the PTK2 molecular signature strongly reflected the activation levels of immune pathways and immune cells. These findings suggested that PTK2 is a molecular target of IPF and the PTK2 molecular signature is an effective IPF prognostic biomarker.

PMID:38053045 | DOI:10.1186/s12931-023-02582-4

Am J Respir Crit Care Med. 2023 Dec 5. doi: 10.1164/rccm.202308-1357OC. Online ahead of print.

ABSTRACT

RATIONALE: Oral microbiota associate with diseases of the mouth and serve as a source of lung microbiota. However, the role of oral microbiota in lung disease is unknown.

OBJECTIVES: To determine associations between oral microbiota and disease severity and death in idiopathic pulmonary fibrosis.

METHODS: We analyzed 16S rRNA gene and shotgun metagenomic sequencing data of buccal swabs from 511 patients with idiopathic pulmonary fibrosis in the multicenter CleanUP-IPF trial. Buccal swabs were collected from usual care, and antimicrobial cohorts. Microbiome data was correlated with measures of disease severity using principal component analysis and linear regression models. Associations between the buccal microbiome and mortality were determined using Cox additive models, Kaplan Meier analysis and Cox proportional hazards models.

MEASUREMENTS AND MAIN RESULTS: Greater buccal microbial diversity associated with lower forced vital capacity (FVC) at baseline [mean diff -3.60: 95% CI -5.92 to -1.29 percent predicted FVC per 1 unit increment]. The buccal proportion of Streptococcus correlated positively with FVC [mean diff 0.80: 95% CI 0.16-1.43 percent predicted per 10% increase] (n=490). Greater microbial diversity was associated with an increased risk of death [HR 1.73: 95% CI 1.03-2.90] while a greater proportion of Streptococcus was associated with a reduced risk of death [HR 0.85: 95% CI 0.73 to 0.99]. The Streptococcus genus was mainly comprised of Streptococcus mitis species.

CONCLUSIONS: Increasing buccal microbial diversity predicts disease severity and death in IPF. The oral commensal Streptococcus mitis spp associates with preserved lung function and improved survival.

PMID:38051927 | DOI:10.1164/rccm.202308-1357OC

EJNMMI Phys. 2023 Dec 5;10(1):77. doi: 10.1186/s40658-023-00595-y.

ABSTRACT

BACKGROUND: Increased pulmonary [Formula: see text]F-FDG metabolism in patients with idiopathic pulmonary fibrosis, and other forms of diffuse parenchymal lung disease, can predict measurements of health and lung physiology. To improve PET quantification, voxel-wise air fractions (AF) determined from CT can be used to correct for variable air content in lung PET/CT. However, resolution mismatches between PET and CT can cause artefacts in the AF-corrected image.

METHODS: Three methodologies for determining the optimal kernel to smooth the CT are compared with noiseless simulations and non-TOF MLEM reconstructions of a patient-realistic digital phantom: (i) the point source insertion-and-subtraction method, [Formula: see text]; (ii) AF-correcting with varyingly smoothed CT to achieve the lowest RMSE with respect to the ground truth (GT) AF-corrected volume of interest (VOI), [Formula: see text]; iii) smoothing the GT image to match the reconstruction within the VOI, [Formula: see text]. The methods were evaluated both using VOI-specific kernels, and a single global kernel optimised for the six VOIs combined. Furthermore, [Formula: see text] was implemented on thorax phantom data measured on two clinical PET/CT scanners with various reconstruction protocols.

RESULTS: The simulations demonstrated that at [Formula: see text] iterations (200 i), the kernel width was dependent on iteration number and VOI position in the lung. The [Formula: see text] method estimated a lower, more uniform, kernel width in all parts of the lung investigated. However, all three methods resulted in approximately equivalent AF-corrected VOI RMSEs (<10%) at [Formula: see text]200i. The insensitivity of AF-corrected quantification to kernel width suggests that a single global kernel could be used. For all three methodologies, the computed global kernel resulted in an AF-corrected lung RMSE <10% at [Formula: see text]200i, while larger lung RMSEs were observed for the VOI-specific kernels. The global kernel approach was then employed with the [Formula: see text] method on measured data. The optimally smoothed GT emission matched the reconstructed image well, both within the VOI and the lung background. VOI RMSE was <10%, pre-AFC, for all reconstructions investigated.

CONCLUSIONS: Simulations for non-TOF PET indicated that around 200i were needed to approach image resolution stability in the lung. In addition, at this iteration number, a single global kernel, determined from several VOIs, for AFC, performed well over the whole lung. The [Formula: see text] method has the potential to be used to determine the kernel for AFC from scans of phantoms on clinical scanners.

PMID:38049611 | DOI:10.1186/s40658-023-00595-y

Heliyon. 2023 Nov 20;9(12):e22565. doi: 10.1016/j.heliyon.2023.e22565. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Early identification of fibrotic interstitial lung disease (F-ILD) patients with high risk of progression will help initiate early therapeutic intervention and potential improvement of outcomes. This study was designed to assess the predictors of progression in patients with F-ILD.

METHODS: Patients with F-ILD in Shanghai Pulmonary Hospital between January 1, 2019 and July 31, 2021 were retrospectively analyzed. The patients enrolled were divided into progressive group and non-progressive group according to the specified criteria. Baseline characteristics were collected and a multivariate regression was conducted to identify independent predictors of progression.

RESULTS: Of the 177 F-ILD cases, 87 were enrolled in the progressive group and 90 were in the non-progressive group. The cohort included 11 types of F-ILD, primarily were connective tissue disease-associated interstitial lung disease (CTD-ILD) (43, 24.3 %), idiopathic pulmonary fibrosis (IPF) (39, 22.0 %), interstitial pneumonia with autoimmune features (IPAF) (32, 18.1 %), and unclassifiable (23, 13.0 %). The highest proportion of progression was seen in nonspecific interstitial pneumonia (NSIP) subgroup (66.7 %), followed by IPF (59.0 %) and HP (57.1 %). After adjusting for gender and age, a course of disease longer than 9.5 months (OR: 2.633; 95 % CI: 1.190-5.826, P = 0.017), lymphocyte in peripheral blood more than 2.24 (109/L) (OR: 2.670; 95 % CI: 1.095-6.510, P = 0.031), and emphysema in high-resolution computed tomography (HRCT) (OR: 2.387; 95 % CI: 1.017-5.640, P = 0.046) were independent predictors of progression in F-ILD patients.

CONCLUSIONS: This study suggested that in patients with F-ILD, long course of disease, elevated blood lymphocyte and emphysema on HRCT were independent predictors of progression, which may suggest utility in early therapeutic intervention.

PMID:38046148 | PMC:PMC10686856 | DOI:10.1016/j.heliyon.2023.e22565

bioRxiv. 2023 Nov 23:2023.11.22.568369. doi: 10.1101/2023.11.22.568369. Preprint.

ABSTRACT

Single-cell RNA-sequencing (scRNA) datasets are becoming increasingly popular in clinical and cohort studies, but there is a lack of methods to investigate differentially expressed (DE) genes among such datasets with numerous individuals. While numerous methods exist to find DE genes for scRNA data from limited individuals, differential-expression testing for large cohorts of case and control individuals using scRNA data poses unique challenges due to substantial effects of human variation, i.e., individual-level confounding covariates that are difficult to account for in the presence of sparsely-observed genes. In this paper, we develop the eSVD-DE, a matrix factorization that pools information across genes and removes confounding covariate effects, followed by a novel two-sample test in mean expression between case and control individuals. In general, differential testing after dimension reduction yields an inflation of Type-1 errors. However, we overcome this by testing for differences between the case and control individuals' posterior mean distributions via a hierarchical model. We benchmark our method's accuracy and power increase compared to other DE methods typically repurposed for analyzing cohort-wide differential expression based on simulated data. We then use the eSVD-DE to study the cohort-wide differential expression in idiopathic pulmonary fibrosis, varying severity of ulcerative colitis, and autism spectrum disorder. Altogether, eSVD-DE proposes a novel and powerful way to test for DE genes among cohorts after performing a dimension reduction.

PMID:38045428 | PMC:PMC10690270 | DOI:10.1101/2023.11.22.568369

Clin J Gastroenterol. 2023 Dec 2. doi: 10.1007/s12328-023-01894-8. Online ahead of print.

ABSTRACT

Revised idiopathic pulmonary fibrosis treatment guidelines were published in 2015, and nintedanib was conditionally recommended. Although diarrhea is reported to be a common major adverse event associated with nintedanib, there have been few reports on detailed endoscopic findings of nintedanib-associated enterocolitis. A 74-year-old woman was diagnosed with idiopathic pulmonary fibrosis 4 years ago in May. She was started on nintedanib (300 mg). Three months later, hepatic dysfunction was observed; therefore, the drug was temporarily discontinued and then resumed at a dose reduction of 200 mg. Five months later, the patient developed diarrhea, and the dose was reduced to 150 mg. However, no effect was noted; hence, colonoscopy was performed. Various inflammatory lesions, such as erythema and erosions, were observed continuously at the rectum, which resembled ulcerative colitis. No improvement was observed 2 months after follow-up colonoscopy, and nintedanib-related enterocolitis was suspected. The dose was further reduced to 100 mg. Since the endoscopic findings of nintedanib-associated enterocolitis are similar to those of ulcerative colitis, it is critical to consider patients with diarrhea who are taking nintedanib as having associated enterocolitis and attempt to reduce or discontinue the drug if diarrhea does not improve with antidiarrheal agents.

PMID:38042763 | DOI:10.1007/s12328-023-01894-8

Int J Pharm. 2023 Nov 29:123644. doi: 10.1016/j.ijpharm.2023.123644. Online ahead of print.

ABSTRACT

Nintedanib (NIN) and pirfenidone are the only approved drugs for the treatment of Idiopathic Pulmonary Fibrosis (IPF). However, NIN and pirfenidone have low oral bioavailability and limited therapeutic potential, requiring higher dosages to increase their efficacy, which causes significant liver and gastrointestinal toxicities. In this study, we aimed to develop nintedanib-loaded solid lipid nanoparticles (NIN-SLN) to improve the oral bioavailability and therapeutic potential against TGF-β-induced differentiation in IPF fibroblasts and bleomycin (BLM)-induced lung fibrosis in rat models. NIN-SLN was prepared using a double-emulsification method and characterization studies (Particle size, zeta potential, entrapment efficiency and other parameters) were performed using various techniques. NIN-SLN treatment significantly (p<0.001) downregulated α-SMA and COL3A1 expression in TGF-β stimulated DHLF and LL29 cells. NIN-SLN showed a 2.87-fold increase in the bioavailability of NIN and also improved the NIN levels in lung tissues compared to NIN alone. Pharmacodynamic investigation revealed that NIN-SLN (50 mg/Kg) treatment significantly attenuated BLM-induced lung fibrosis by inhibiting epithelial-to-mesenchymal-transition (EMT), extracellular matrix remodelling, and collagen deposition compared to free NIN. Additionally, in the BLM model of fibrosis, NIN-SLN greatly improved the BLM-caused pathological changes, attenuated the NIN-induced gastrointestinal abnormalities, and significantly improved the lung functional indices compared to free NIN. Collectively, NIN-SLN could be a promising nanoformulation for the management of pulmonary fibrosis.

PMID:38040396 | DOI:10.1016/j.ijpharm.2023.123644

Front Immunol. 2023 Nov 14;14:1268141. doi: 10.3389/fimmu.2023.1268141. eCollection 2023.

ABSTRACT

BACKGROUND: Cuproptosis, the most recently identified and regulated cell death, depends on copper ions in vivo. Copper regulates the pathogenesis of Idiopathic pulmonary fibrosis (IPF), but the mechanism of action underlying cuproptosis in IPF remains unclear.

METHODS: We identified three cuproptosis patterns based on ten cuproptosis-related genes using unsupervised consensus clustering. We quantified these patterns using a PCA algorithm to construct a cuproptosis score. ssGSEA and the Cibersort algorithm assessed the immune profile of IPF patients. GSEA and GSVA were used to analyze the functional differences in different molecular patterns. Drug susceptibility prediction based on cuproptosis scores and meaningful gene markers was eventually screened in combination with external public data sets,in vitro experiments and our cases.

RESULTS: Of the three types of cuproptosis-related clusters identified in the study, patients in the clusterA, geneclusterB, and score-high groups showed improved prognoses. Moreover, each cluster exhibited differential immune characteristics, with the subtype showing a poorer prognosis associated with an immune overreaction. Cuproptosis score can be an independent risk factor for predicting the prognosis of IPF patients. GSEA showed a significant functional correlation between the score and cuproptosis. The genes AKAP9, ANK3, C6orf106, LYRM7, and MBNL1, were identified as prognostic-related signatures in IPF patients. The functional role of immune regulation in IPF was further explored by correlating essential genes with immune factors. Also, the nomogram constructed by cumulative information from gene markers and cuproptosis score showed reliable clinical application.

CONCLUSIONS: Cuproptosis patterns differ significantly in the prognosis and immune characteristics of IPF patients. The cuproptosis score and five gene signatures can provide a reliable reference in the prognosis and diagnosis of IPF.

PMID:38035073 | PMC:PMC10682708 | DOI:10.3389/fimmu.2023.1268141

BMC Pulm Med. 2023 Nov 29;23(1):479. doi: 10.1186/s12890-023-02778-w.

ABSTRACT

BACKGROUND: Numerous studies have demonstrated the potential of pirfenidone to enhance the prognosis of patients afflicted with idiopathic pulmonary fibrosis (IPF). Although N-acetylcysteine (NAC) is utilized as an antioxidant in IPF treatment, the combination of NAC and pirfenidone has produced inconsistent outcomes in certain studies. To assess the clinical effectiveness and safety of NAC plus pirfenidone (designated as the treatment group) versus pirfenidone monotherapy (designated as the control group), we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs).

METHODS: RCTs of NAC plus pirfenidone were reviewed searching from databases and networks of unpublished and published studies in any language. Using pair-wise meta-analysis, changes in pulmonary function test (PFT) parameters and safety were evaluated.

RESULTS: Two independent reviewers selected and obtained data from 5 RCTs (n = 398), comprising 1 study from Japan, 1 from Europe, and 3 from China. NAS plus pirfenidone as compared to pirfenidone monotherapy for IPF may not reduce the incidence of skin effects(RR 1.26 [95%CI 0.64 to 2.45]) and mortality(RR 0.35 [95%CI 0.07 to 1.68])(both moderate certainty). NAS plus pirfenidone as compared to pirfenidone monotherapy for IPF may not reduce the incidence of at least one side effects(RR 1.00 [95%CI 0.84 to 1.19]; low certainty),severe side effects(RR 0.67 [95%CI 0.30 to 1.47]; low certainty) and gastrointestinal effects(RR 0.67 [95%CI 0.41 to 1.09]; low certainty) with possibly no effect in Δ%DLco(SMD -0.17 [95%CI -0.15 to 0.48]; low certainty). Meanwhile, the effect of NAS plus pirfenidone as compared to pirfenidone monotherapy on ΔFVC(SMD 0.18 [95%CI -0.68 to 1.05]), Δ%FVC(SMD -2.62 [95%CI -5.82 to 0.59]) and Δ6MWT(SMD -0.35 [95%CI -0.98 to 0.28]) is uncertain(extremely low certainty).

CONCLUSION: Moderate certainty evidence suggests that NAS plus pirfenidone, compared to pirfenidone monotherapy for IPF, does not reduce the incidence of skin effects and mortality.

PMID:38031002 | DOI:10.1186/s12890-023-02778-w

Chest. 2023 Nov 27:S0012-3692(23)05827-0. doi: 10.1016/j.chest.2023.11.035. Online ahead of print.

ABSTRACT

BACKGROUND: Antifibrotics are effective in slowing forced vital capacity (FVC) decline in idiopathic pulmonary fibrosis (IPF). However, whether antifibrotic type is differentially associated with FVC decline remains inconclusive.

RESEARCH QUESTION: Are there significant differences in 12-month FVC decline between pirfenidone and nintedanib?

STUDY DESIGN AND METHODS: A post-hoc analysis was performed using CleanUP-IPF trial (NCT02759120). Participants who reported using pirfenidone or nintedanib upon enrollment into the trial were in the primary analysis. Spirometry was scheduled at baseline, 12-, and 24-month study visit. Linear mixed-effects models with random intercept and slope were used to examine changes in FVC over time. Models were adjusted for age, sex, smoking history, coronary artery disease history, baseline FVC, and 12-month spline term were used. Survival and non-elective respiratory hospitalization by antifibrotic type were determined using Cox regression models with adjustment for age, sex, smoking history, coronary artery disease history, and baseline FVC and diffusing capacity for carbon monoxide.

RESULTS: Out of the 513 participants with IPF randomized in CleanUP-IPF, 407 reported using pirfenidone (n=264, 65%) or nintedanib (n=143, 35%). The pirfenidone group had more participants with a history of coronary artery disease than nintedanib (34.1% vs. 20.3%). Nintedanib-treated patients had a higher 12-month visit FVC compared with pirfenidone treated patients (mean difference 106 mL; 95% CI 34-178). This difference was attenuated at the 24-month study visit. There were no significant differences in overall survival and non-elective respiratory hospitalization between pirfenidone and nintedantib treated groups.

INTERPRETATION: Patients with IPF who used nintedanib had a slower 12-month FVC decline than pirfenidone in a post-hoc analysis of a clinical trial.

PMID:38030064 | DOI:10.1016/j.chest.2023.11.035

Am J Respir Cell Mol Biol. 2023 Nov 29. doi: 10.1165/rcmb.2023-0151OC. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive disease with elusive molecular mechanisms and limited therapeutic methods. Aberrant activation of fibroblasts is a central hallmark of lung fibrosis. Here we report that Golgi membrane protein 1 (GOLM1, also known as GP73 or GOLPH2), was elevated in both lungs of patients with pulmonary fibrosis and bleomycin (BLM)-induced pulmonary fibrotic mice. Loss of GOLM1 inhibited proliferation, differentiation, and extracellular matrix (ECM) deposition of fibroblasts, while overexpression of GOLM1 exerted the opposite effects. Similarly, worsening pulmonary fibrosis post-BLM treatment were observed in GOLM1 knock-in (GOLM1KI/KI) mice, while BLM-treated GOLM1 knock-out (GOLM1KO/KO) mice exhibited alleviated pulmonary fibrosis and collagen deposition. Furthermore, we identified long noncoding RNA (lncRNA) NEAT1 downstream of GOLM1 as a potential mediator of pulmonary fibrosis through increased GOLM1 expression. Depletion of NEAT1 inhibited fibroblast proliferation and ECM production and reversed the profibrotic effects of GOLM1 overexpression. Additionally, we identified KLF4 as a downstream mediator of GOLM1 signaling to NEAT1. Our findings suggest that GOLM1 plays a pivotal role in promoting pulmonary fibrosis through GOLM1-KLF4-NEAT1 signaling axis. Targeting GOLM1 and its downstream pathways may represent novel therapeutic strategies for treating pulmonary fibrosis.

PMID:38029327 | DOI:10.1165/rcmb.2023-0151OC

Heliyon. 2023 Nov 3;9(11):e20914. doi: 10.1016/j.heliyon.2023.e20914. eCollection 2023 Nov.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an incurable chronic progressive disease with a low survival rate and ineffective therapeutic options. We examined the effects of imrecoxib, a nonsteroidal anti-inflammatory drug, on experimental pulmonary fibrosis. The mouse IPF model was established by intratracheal instillation of bleomycin. From Day 0 to Day 13, the mice were orally administered imrecoxib (100 mg/kg) and pirfenidone (200 mg/kg) daily, and from Day 7 to Day 13, the mice were orally administered pirfenidone and imrecoxib daily. The tissues were dissected on the 14th day. Mouse body weight was measured, and histopathological examination and hydroxyproline content analysis confirmed that the administration of imrecoxib exerted a similar effect to pirfenidone. Compared with bleomycin-induced mice, imrecoxib-treated mice showed significantly reduced inflammatory factor expression (IL-1 and TNF-α) and inflammatory cell numbers (macrophages, lymphocytes, and neutrophils) in BALF (bronchoalveolar lavage fluid). Our experiment tested the ability of imrecoxib to inhibit the signal pathway involved in gene expression induced by TGF-β1 in the NIH-3T3 cell line in vitro. Western blotting showed that imrecoxib (20 μM and 40 μM) inhibited the expression of fibronectin, type I collagen and CTGF. In addition, imrecoxib reduced the levels of p-ERK1/2. The changes in the expression of related proteins in mouse lung tissue were similar to those in cells. In summary, our findings suggested that the administration of imrecoxib prevented and treated murine IPF by inhibiting inflammation and the TGF-β1-ERK1/2 signaling pathway.

PMID:38027732 | PMC:PMC10663740 | DOI:10.1016/j.heliyon.2023.e20914

Heliyon. 2023 Oct 31;9(11):e21538. doi: 10.1016/j.heliyon.2023.e21538. eCollection 2023 Nov.

ABSTRACT

STUDY DESIGN AND OBJECTION: Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disease characterized by damage to alveolar epithelial cells and abnormal deposition of the extracellular matrix. Although the disease course for most patients with IPF is progressive, in some cases the disease may appear as an acute exacerbation. Mechanical ventilation life support plays an important role in the treatment of patients with IPF but is associated with an increased risk of acute exacerbation of IPF (AE-IPF). Treatment is controversial and is not supported by sufficient clinical evidence. AE-IPF after lung cancer surgery is extremely rare, and the etiology and mechanism remain unclear, and its clinical manifestations are very similar to acute pulmonary edema and are easily misdiagnosed.

SUMMARYOF BACKGROUND DATA: We describe a 66-year-old male patient with IPF complicated with lung cancer who underwent thoracoscopic resection of the right upper lobe of the lung. Seventy-two hours after surgery, chest computed tomography indicated that AE-IPF in the mechanically ventilated lung was significantly greater than that in the operated lung. The patient's own lung was used as a control and proved that mechanical ventilation can lead to AE-IPF.

RESULTS AND CONCLUSIONS: By highlighting the clinical characteristics of patients with acute exacerbation of idiopathic pulmonary fibrosis, this article will enhance the vigilance of clinicians on AE-IPF caused by mechanical ventilation. Importantly, preoperative nintedanib therapy should be applied in advance to prevent AE-IPF on in patients with mild IPF. Precise pulmonary protective ventilation strategies need to be formulated for patients with IPF to reduce mortality.

PMID:38027643 | PMC:PMC10665659 | DOI:10.1016/j.heliyon.2023.e21538

iScience. 2023 Oct 27;26(11):108345. doi: 10.1016/j.isci.2023.108345. eCollection 2023 Nov 17.

ABSTRACT

Autoimmunity plays a role in certain types of lung fibrosis, notably connective tissue disease-associated interstitial lung disease (CTD-ILD). In idiopathic pulmonary fibrosis (IPF), an incurable and fatal lung disease, diagnosis typically requires clinical exclusion of autoimmunity. However, autoantibodies of unknown significance have been detected in IPF patients. We conducted computational analysis of B cell transcriptomes in published transcriptomics datasets and developed a proteomic Differential Antigen Capture (DAC) assay that captures plasma antibodies followed by affinity purification of lung proteins coupled to mass spectrometry. We analyzed antibody capture in two independent cohorts of IPF and CTL-ILD patients over two disease progression time points. Our findings revealed significant upregulation of specific immunoglobulins with V-segment bias in IPF across multiple cohorts. We identified a predictive autoimmune signature linked to reduced transplant-free survival in IPF, persisting over time. Notably, autoantibodies against thrombospondin-1 were associated with decreased survival, suggesting their potential as predictive biomarkers.

PMID:38026226 | PMC:PMC10661358 | DOI:10.1016/j.isci.2023.108345