J Innate Immun. 2024 Dec 11:1-14. doi: 10.1159/000543083. Online ahead of print.

ABSTRACT

BACKGROUND: Interstitial lung diseases (ILD) are poorly understood disorders characterised by diffuse damage to the lung parenchyma, with inflammation and fibrosis. Some manifest a progressive fibrotic phenotype with high fatality and limited treatment options, such as idiopathic pulmonary fibrosis (IPF).

SUMMARY: The degree to which inflammation plays a role in fibrosis progression is unknown. However, wound healing and fibrosis are intricate processes influenced by various inflammatory factors. Extracellular nucleosides and nucleotides, including adenosine triphosphate (ATP), activate pro-inflammatory responses of innate immunity and are widely implicated in tissue fibrosis across different organs. The pro-inflammatory effects of extracellular nucleotides occur via P1 and P2 purinergic receptors, expressed across the lung and immune system, and have been implicated in various pulmonary diseases including pulmonary fibrosis. This review amalgamates available data on the complex role of P1 and P2 purinergic receptor signalling in pulmonary fibrosis and discusses perspectives for novel treatments.

KEY MESSAGES: Purinergic signalling plays a complex and pivotal role in pulmonary fibrosis, warranting further study. The intricate interplay between P1 and P2 receptor pathways necessitates a comprehensive approach to understand their collective impact. While evidence from preclinical models is promising, human studies are essential for further understanding in pulmonary fibrosis. Advances in receptor-specific agonists and antagonists provide novel avenues for research and may ultimately lead to new therapies for patients.

PMID:39662078 | DOI:10.1159/000543083

J Bras Pneumol. 2024 Dec 6;50(5):e20240058. doi: 10.36416/1806-3756/e20240058. eCollection 2024.

ABSTRACT

OBJECTIVE: The frequency of obstructive sleep apnea (OSA) in patients with idiopathic pulmonary fibrosis (IPF) is high. The clinical course of non-IPF interstitial lung disease (ILD) can be similar to that of IPF. We sought to assess the frequency and predictors of OSA in patients with non-IPF fibrotic ILD, as well as the impact of positive airway pressure (PAP) therapy on the quality of life of such patients.

METHODS: This was a prospective study in which non-IPF fibrotic ILD patients underwent a home sleep apnea test. The patients with and without OSA were compared, and a multivariate logistic regression model was used to identify independent predictors of OSA. At 3 months after initiation of PAP therapy, we evaluated the participating patients for respiratory events, nocturnal hypoxemia, and changes in quality of life.

RESULTS: Of a total of 50 patients, 50% were male, and 76% were diagnosed with OSA. The mean age was 67.8 ± 8.3 years. The patients with OSA had significantly lower TLC (p = 0.033) and awake SpO2 (p = 0.023) than did those without OSA. In the multivariate logistic regression model, SpO2 (OR = 0.46; p = 0.016) and TLC (OR = 0.95; p = 0.026) remained significantly associated with OSA risk. A total of 12 patients received PAP therapy. At 3 months after initiation of PAP therapy, 91.7% were well controlled, Epworth Sleepiness Scale scores decreased significantly (p = 0.006), and emotional well-being tended to improve (p = 0.068). PAP therapy corrected nocturnal hypoxemia in all patients.

CONCLUSIONS: We found a high frequency of OSA in patients with non-IPF fibrotic ILD. A low TLC was an independent predictor of a higher risk of OSA. PAP therapy can correct nocturnal hypoxemia. There should be a low threshold for suspicion of OSA and initiation of PAP therapy in patients with non-IPF fibrotic ILD.

PMID:39661832 | DOI:10.36416/1806-3756/e20240058

Asian J Pharm Sci. 2024 Aug;19(4):100944. doi: 10.1016/j.ajps.2024.100944. Epub 2024 Jul 14.

ABSTRACT

Mesenchymal stem cells (MSCs) have emerged as promising candidates for idiopathic pulmonary fibrosis (IPF) therapy. Increasing the MSC survival rate and deepening the understanding of the behavior of transplanted MSCs are of great significance for improving the efficacy of MSC-based IPF treatment. Therefore, dual-functional Au-based nanoparticles (Au@PEG@PEI@TAT NPs, AuPPT) were fabricated by sequential modification of cationic polymer polyetherimide (PEI), polyethylene glycol (PEG), and transactivator of transcription (TAT) penetration peptide on AuNPs, to co-deliver retinoic acid (RA) and microRNA (miRNA) for simultaneously enhancing MSC survive and real-time imaging tracking of MSCs during IPF treatment. AuPPT NPs, with good drug loading and cellular uptake abilities, could efficiently deliver miRNA and RA to protect MSCs from reactive oxygen species and reduce their expression of apoptosis executive protein Caspase 3, thus prolonging the survival time of MSC after transplantation. In the meantime, the intracellular accumulation of AuPPT NPs enhanced the computed tomography imaging contrast of transplanted MSCs, allowing them to be visually tracked in vivo. This study establishes an Au-based dual-functional platform for drug delivery and cell imaging tracking, which provides a new strategy for MSC-related IPF therapy.

PMID:39660166 | PMC:PMC11630633 | DOI:10.1016/j.ajps.2024.100944

Sarcoidosis Vasc Diffuse Lung Dis. 2024 Dec 10;41(4):e2024051. doi: 10.36141/svdld.v41i4.15198.

ABSTRACT

BACKGROUND: Interstitial lung diseases have high mortality associated with hospitalization for decompensation. There are doubts about the factors involved in the progression of fibrosis, for example the role played by acute exacerbations. With this work, the authors intend to analyze whether there are predictive parameters of mortality related to exacerbations.

METHODS: A retrospective study was carried out of patients admitted to the Pulmonology department of Coimbra University Hospital Center for exacerbation of fibrosing lung disease between January 2019 and December 2020. These were classified as: idiopathic pulmonary fibrosis (IPF), fibrosing hypersensivity pneumonitis (FHP) and other fibrosing lung diseases. Statistical analysis was performed using SPSS 26.0 considering statistically significant p<0.05 values.

RESULTS: The results show that IPF is associated with longer hospital stay in relation to fibrosing HP and other fibrosing lung diseases mean of 20.93 days (95% CI: 14.69-27.18) vs 11.8 days (95% CI: 1.05-17.22, p=0.023) vs 12.23 days (95% CI 2.06-15.34, p=0.007), respectively. Regarding mortality, there was no difference between IPF, PH and other fibrosing diseases (p=0.631).

CONCLUSION: This study demonstrated that IPF, compared to PH and other fibrosing diseases, is associated with longer hospital stays, probably due to its progressive course despite the institution of corticosteroid therapy. As shown in previous studies, it was concluded that there is no difference in terms of mortality between IPF exacerbations and other forms of fibrosing lung disease.

PMID:39655596 | DOI:10.36141/svdld.v41i4.15198

Sarcoidosis Vasc Diffuse Lung Dis. 2024 Dec 10;41(4):e2024050. doi: 10.36141/svdld.v41i4.15675.

ABSTRACT

BACKGROUND AND AIM: Lung cancer is one of the significant comorbidities seen in patients with Idiopathic Pulmonary Fibrosis (IPF). However, there is limited data on non-IPF Pulmonary Fibrosis (PF) patients with lung cancer (LC). The present study aims to compare the characteristics and survival outcomes of patients diagnosed with LC in IPF and non-IPF PF.

METHODS: The multicenter data records of IPF and non-IPF PF patients diagnosed with lung cancer between 2010- 2022 were analyzed in this descriptive, cross-sectional, and retrospective study.

RESULTS: Of the 251 patients involved in this study [164 IPF-LC, 87 non-IPF PF-LC], 89.6% were male, the mean age was 69±7.9 years and the smoking rate was 85.7%. Honeycomb pattern was more frequently observed in IPF-LC patients [62.8%,37.9%p<0.001], whereas ground-glass opacity [33.5%,59.8%p<0.001] and emphysema [37.8%,59.8%p<0.001] were more frequently seen in non-IPF PF-LC patients. The most commonly seen histological type was squamous cell carcinoma [42.7%,33.9%], followed by adenocarcinoma [28.2%; 32.2%]. [46.4%;47.2%] and their 5-year mortality rates were high [64.6%, 63.2%]. The median survival for both groups was 2±0.22 years [median 95% CI (1.55-2.44)]. The shortest survival time was observed in non-IPF PF-LC subgroup with unclassified PF [1±0.253 years median 95% CI (0.50-1.49) (p=0.030)].

CONCLUSIONS: The majority of IPF and non-IPF PF LC patients were male, elderly, and had a high smoking rate. Squamous cell carcinoma was the most frequently seen histological type and they had short survival periods and high mortality rates. The survival period of unclassified non-IPF PF-LC patients was found to be the shortest.

PMID:39655590 | DOI:10.36141/svdld.v41i4.15675

ERJ Open Res. 2024 Dec 9;10(6):00411-2024. doi: 10.1183/23120541.00411-2024. eCollection 2024 Nov.

ABSTRACT

INTRODUCTION: Exertion-induced desaturation (EID) is a common complication of numerous pulmonary disorders and often treated with supplementary oxygen during exertion. We performed a systematic review and meta-analysis of randomised clinical trials (RCTs) to evaluate the efficacy of supplementary oxygen for EID in pulmonary disorders.

MATERIAL AND METHODS: Medline and Embase were systematically searched from July 2022 to June 2023 following PRISMA guidelines. RCTs that met predefined inclusion criteria were included. Means and standard deviations were extracted and standardised mean differences (SMDs), the difference in means between groups divided by the standard deviation, and 95% confidence intervals were calculated. Exercise capacity was the primary outcome; exercise dyspnoea, baseline dyspnoea and quality of life were secondary objectives. The immediate, post-rehabilitation, short-term and ambulatory effects of oxygen supplementation were evaluated.

RESULTS: We included 15 studies in our analysis. Oxygen supplementation to treat adult EID had been investigated for COPD and idiopathic pulmonary fibrosis (IPF) only. Oxygen supplementation was superior to placebo for its immediate effect on exercise capacity for COPD (SMD 0.42, 95% CI 0.15-0.69, I2=3%) and IPF (SMD 0.41, 95% CI 0.08-0.75, I2=57%) and exercise dyspnoea for COPD (SMD -0.40, 95% CI -0.76--0.04, I2=31%). Sensitivity analysis revealed similar results.

CONCLUSIONS: Our study revealed the efficacy of supplemental oxygen for EID and only a positive immediate effect on exercise capacity and dyspnoea, but no improvement in other short-term or long-term measures.

PMID:39655174 | PMC:PMC11626617 | DOI:10.1183/23120541.00411-2024

ERJ Open Res. 2024 Dec 9;10(6):00553-2024. doi: 10.1183/23120541.00553-2024. eCollection 2024 Nov.

ABSTRACT

INTRODUCTION: Progressive pulmonary fibrosis (PPF) corresponds to any fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF) that presents clinical, physiological and/or radiological evidence of disease progression similar to IPF. Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of pulmonary fibrosis and are associated with disease progression and reduced survival in IPF and other fibrotic ILDs. This study aimed to investigate the role of serum levels of MMP-1 and MMP-7 in patients with fibrotic non-IPF ILD as possible biomarkers of patients at risk of developing PPF.

METHODS: Newly diagnosed patients with fibrotic non-IPF ILD were included in this study. Serum levels of MMP-1 and MMP-7 were quantified at baseline and disease progression was monitored. PPF was defined according to the recent European Respiratory Society, American Thoracic Society, Japanese Respiratory Society and the Latin American Thoracic Society Clinical Practice Guidelines.

RESULTS: 79 patients with fibrotic non-IPF ILDs were included and classified as having PPF or non-PPF. Significantly higher levels of MMP-7, but not MMP-1, were detected in the PPF group (p=0.01). MMP-7 was independently associated with PPF (adjusted OR 1.263, 95% CI 1.029-1.551; p=0.026) after adjustment for sex, age and smoking history. A cut-off value of 3.53 ng·mL-1 for serum MMP-7 levels had a sensitivity of 61% and a specificity of 74% for predicting PPF in non-IPF ILDs.

CONCLUSIONS: In patients with fibrotic non-IPF ILDs, serum MMP-7 levels were significantly greater in the subgroup of patients meeting the PPF criteria at follow-up. This can be considered and further investigated as a possible biomarker to identify fibrotic ILD patients at risk of PPF.

PMID:39655167 | PMC:PMC11626614 | DOI:10.1183/23120541.00553-2024

Bioorg Chem. 2024 Dec 7;154:108017. doi: 10.1016/j.bioorg.2024.108017. Online ahead of print.

ABSTRACT

Tyrosine kinase inhibitors (TKIs) represent a pivotal class of targeted therapies in oncology, with multiple generations developed to address diverse molecular targets. Imatinib is the first TKI developed to target the BCR-ABL1 chimeric protein, which is the key driver oncogene implicated in Philadelphia chromosome-positive chronic myeloid leukemia (CML). Several second-generation tyrosine kinase inhibitors (2GTKIs), such as nilotinib, dasatinib, bosutinib, and radotinib (RTB), followed the groundbreaking introduction of imatinib. RTB occupies the unique position of being the least explored member of this class. While nilotinib, dasatinib, and bosutinib have garnered significant attention and extensive research focus, RTB remains relatively uncharted in comparison to its counterparts. Fundamental drug characteristics, such as the pharmacokinetic and pharmacodynamic properties of RTB, remain unavailable in existing sources. Compared to other 2GTKIs, RTB has been less utilized in combinatorial drug studies, and no investigations have been reported on its effects on solid tumors to date. However, the effects of RTB have been studied in acute myeloid leukemia (AML), multiple myeloma (MM), Parkinson's disease, and idiopathic pulmonary fibrosis (IPF). Although RTB has been investigated in some conditions, these studies are still in their preliminary stages and are comparatively lesser than studies on other 2GTKIs. This review is the first attempt that extensively presents a compilation of data on RTB and describes its therapeutic potential against blood and solid tumors. Further investigations on RTB could expand its chemotherapeutic usage in various solid tumors and enhance the possibility of drug repurposing in cancer therapy.

PMID:39647393 | DOI:10.1016/j.bioorg.2024.108017

Respir Investig. 2024 Dec 7;63(1):81-85. doi: 10.1016/j.resinv.2024.11.018. Online ahead of print.

ABSTRACT

BACKGROUND: Surgical lung biopsy (SLB) is recommended for diagnosing idiopathic pulmonary fibrosis in patients with interstitial lung disease (ILD). The safety of SLB is controversial, as the reported mortality and mobility vary according to the patient's background. This study aimed to assess SLB safety using eligibility criteria that excluded patients at the risk of postoperative complications, including acute exacerbations.

METHODS: We retrospectively reviewed 94 patients with ILD who underwent SLB at our institution between 2010 and 2021. Two peripheral lung locations were resected using 3-port video-assisted thoracoscopic surgery. Complications within 30 and 90 days after surgery were evaluated based on the Clavien-Dindo classification. Preoperative high-resolution computed tomography findings were evaluated according to the guidelines of the American Thoracic Society, 2018. Patients with a radiological usual interstitial pneumonia (UIP) pattern, preoperative oxygen dependence, or organ failure incompatible with general anesthesia were excluded from the study.

RESULTS: The median age of the patients was 66 years. The median vital capacity percentage was 81.0%. The following radiological patterns were observed: UIP, 0%; probable UIP, 30%; indeterminate UIP, 14%; and alternative diagnoses, 56%. The median operative time was 45 min. The 30- and 90-day mortality rates were both 0%. One patient (1%) developed an acute exacerbation of ILD on postoperative day 66. Other grade ≥ III complications were observed in 4 cases (4%), 3 of which were associated with air leakage. Home oxygen therapy was not initiated.

CONCLUSIONS: By excluding patients with poor SLB indications, our criteria are suggested to be valid for safe SLB.

PMID:39647322 | DOI:10.1016/j.resinv.2024.11.018

Eur Radiol. 2024 Dec 8. doi: 10.1007/s00330-024-11209-1. Online ahead of print.

ABSTRACT

OBJECTIVES: Recent studies suggest the existence of an idiopathic pulmonary arterial hypertension (IPAH) phenotype affecting mostly patients with a smoking history, characterised by low diffusion capacity for carbon monoxide (DLCO) without clinically significant emphysema. This study's objective was to test the hypothesis of a loss of pulmonary capillaries as an underlying mechanism by comparison to other patient groups with and without pulmonary hypertension (PH).

MATERIALS AND METHODS: Between March 2019 and June 2023, patients of four groups were recruited for this observational study: IPAH with preserved (1) and low DLCO (2), combined pulmonary fibrosis and emphysema with PH (3), and emphysema without PH (4). Patients underwent clinical CT and 129Xe MRI including dissolved-phase imaging yielding the ratio of 129Xe in red blood cells and membrane tissues (RBC-M), chemical shift saturation recovery for determining RBC fraction η and diffusion-weighted imaging yielding surface-volume ratio. Kruskal-Wallis tests were used for statistical analysis.

RESULTS: Twenty-nine participants were recruited, of which 22 (age 64 ± 10, 11 male, 5/5/7/5 for the individual groups) could be included in the analysis. RBC-M and η were reduced in IPAH with low versus preserved DLCO and emphysema groups (p ≤ 0.01). CT low-attenuation area percentage was not increased in IPAH with low DLCO compared to any group. 129Xe MRI-derived surface-volume ratio was reduced in IPAH with low versus preserved DLCO (p = 0.04).

CONCLUSION: Results are consistent with a loss of pulmonary capillaries in patients with IPAH and low DLCO along with destruction of alveolar tissue, likely due to early diffuse emphysema.

KEY POINTS: Question A loss of pulmonary capillaries has been suggested in patients with IPAH and low diffusion capacity without clinically significant emphysema on CT. Findings 129Xe uptake in red blood cells and lung surface-volume ratio were reduced in IPAH patients with low compared to preserved diffusion capacity. Clinical relevance This study furthers the understanding of the underlying pathological mechanisms in IPAH with low diffusion capacity, providing evidence that loss of pulmonary capillaries is accompanied by alveolar tissue destruction despite near-normal CT.

PMID:39645621 | DOI:10.1007/s00330-024-11209-1

Exp Lung Res. 2024;50(1):278-289. doi: 10.1080/01902148.2024.2437377. Epub 2024 Dec 7.

ABSTRACT

Purpose/Aim: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia. Multiple genetic factors, environmental exposures, micro-aspirations secondary to gastroesophageal reflux, age, sex, smoking habit, and infections contribute to its etiology; consequently, its pathogenesis remains unclear. The homeostasis of gut microbiota, including bacteria, archaea, and fungi, can influence the functions of both the intestine and remote organs. There are still many unknowns regarding the effects and mechanisms of gut microbiota dysbiosis on the development of IPF. In this study, we aimed to characterize the gut microbiota of patients with IPF compared with that of healthy controls. Furthermore, we assessed the effects of antifibrotic drugs on gut dysbiosis. Materials and Methods: This study involved 12 patients with IPF receiving antifibrotic drug therapy, 12 patients with IPF not receiving antifibrotic drug therapy, and 8 healthy controls. The clinical parameters of the patients were recorded, and DNA extracted from stool samples was subjected to 16S ribosomal RNA gene sequencing of the V1-V9 hypervariable regions. Results: Campylobacterota species were detected in the patient groups but not in the control group. Staphylococcales and Gemellaceae species were not detected in the IPF groups; however, a significant relationship was observed in the control group. In the IPF groups, Actinobacteria, Bifidobacteriales, Burkholderiales, Bacteroidaceae, Dorea, Fusicatenibacter, and Ruminococcus -gauvreauii abundance was low and Enterobacterales, Erysipelotrichaceae, Holdemanella, and Alloprevotella abundance was high compared with those in the control group. When the IPF group using antifibrotic drugs and that not using antifibrotic drugs were compared, only Lachnospiraceae UCG 004 abundance was found to be lower in the patient group receiving antifibrotic drugs. Conclusions: Patients with IPF exhibit higher or lower abundance of certain taxa compared to healthy controls, providing novel perspectives on the pathogenesis and treatment of various illnesses. Examining changes in intestinal microbiota during treatment may guide the clinical strategy for managing adverse effects.

PMID:39644491 | DOI:10.1080/01902148.2024.2437377

Int Immunopharmacol. 2024 Dec 5;145:113688. doi: 10.1016/j.intimp.2024.113688. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a prevalent chronic lung condition of unknown etiology characterized by fibrosis and inflammation. Lung scarring progresses owing to cytokines and immune cells that promote inflammation and fibrosis in idiopathic pulmonary fibrosis (IPF). The anti-inflammatory and anti-fibrotic properties of the ethyl acetate extract of Clerodendrum phlomidis (CPEA), derived from the Indian plant "agnimantha," are recognized in traditional Ayurvedic medicine. This study investigated the potential protective mechanisms of Clerodendrum phlomidis (CPEA), which have not been previously examined, and demonstrated how CPEA affects bleomycin (BLM)-induced lung fibrosis. Phytometabolomic analysis of Clerodendrum phlomidis was performed using UPLC-ESI-Q/TOF-MS. Free radical scavenging assays were also used to evaluate the antioxidant capacity of the plants using ABTS, DPPH, FRAP, and NO assays. Using ELISA and Griess reagent assays, we assessed the anti-inflammatory effects of CPEA in LPS-induced Jurkat, THP-1, and LL-29 cell lines. This study compared intratracheal injection of BLM-induced IPF in Wistar rats with oral administration of CPEA extract for its anti-fibrotic and anti-inflammatory properties. Multiple techniques were employed, including enzyme-linked immunosorbent assay (ELISA), hydroxyproline, histopathological, biochemical, antioxidant enzyme profiling, and hematological analyses. Polyphenolic compounds were identified using qualitative CPEA. Plant extracts demonstrated free radical-scavenging activity in vitro and exhibited antioxidant properties. CPEA extract reduced TNF-α, IL-1β, and NO levels in LPS-stimulated Jurkat, THP-1, and LL-29 cells. In response to BLM-induced lung and serum conditions in Wistar rats, the CPEA extract significantly reduced (p < 0.05) markers of inflammation and fibrosis (ALP, LDH, TNF-α, CXCL8-MIP2, MMP7, SP-A, SP-D, NO, TBARS, and MPO) and significantly restored antioxidant enzymes (p < 0.05) (GSH, GPx, and GST) and anti-inflammatory cytokines (IL10). Oral CPEA extract attenuates fibrosis, inflammation, oxidative stress, nitrosative stress, and lipid peroxidation in BLM-induced idiopathic pulmonary fibrosis (IPF). CPEA extract improved lung function and increased survival rates. Clinical trials are necessary, as this study indicated that the dietary flavonoid-rich component of CPEA extracts possesses anti-inflammatory and antioxidant properties. CPEA extract restored antioxidant enzyme levels and exerted anti-fibrotic and anti-inflammatory effects in rats with idiopathic lung fibrosis induced by BLM. CPEAs protect against lipopolysaccharide (LPS)-induced inflammation in vitro and bleomycin-induced idiopathic pulmonary fibrosis (IPF) in vivo. The findings of our investigation indicate that CPEA demonstrates therapeutic potential for IPF in human subjects, as evidenced by its capacity to enhance antioxidant, anti-inflammatory, and anti-fibrotic markers in preclinical disease models.

PMID:39642567 | DOI:10.1016/j.intimp.2024.113688

Am J Respir Cell Mol Biol. 2024 Dec 6. doi: 10.1165/rcmb.2024-0372TR. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) and lung fibrosis secondary to infections such as influenza A and COVID-19 have limited treatment options outside of supportive therapy and lung transplantation. Multiple lung stem cell populations have been implicated in the pathogenesis of lung fibrosis, and more progenitor cell populations continue to be discovered and characterized. In this review, we summarize the functions and differentiation pathways of various cells that comprise the lung epithelium. We then focus on two subpopulations of KRT5+ or KRT8+ transitional cells that both originate from alveolar type II cells but experience different cell fates and play important roles in lung regeneration and repair. We address these transitional cells' potential role in fibrosis and bronchiolization of the alveoli, as they are correlated to aggregate near fibrotic foci in both in vivo models and in human fibrotic lung disease. We conclude by discussing recent advances in cell and organoid therapy to replace aberrant transitional cells and treat lung fibrosis. Namely, we focus on strategies to minimize immune clearance of transplanted cells and to optimize engraftment by transplanting cells pre-cultured as 3D organoids.

PMID:39642382 | DOI:10.1165/rcmb.2024-0372TR

Am J Respir Cell Mol Biol. 2024 Dec 6. doi: 10.1165/rcmb.2024-0255OC. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by the sustained activation of interstitial fibroblasts leading to excessive collagen deposition and progressive organ failure. Epigenetic and metabolic abnormalities have been shown to contribute to the persistent activated state of scar-forming fibroblasts. However, how epigenetic changes regulate fibroblast metabolic responses to promote fibroblast activation and progressive fibrosis remains largely unknown. Here we show that the epigenetic regulator chromobox protein homolog 5 (CBX5) is critical to the transition of quiescent fibroblasts to activated collagen-producing fibroblasts in response to bleomycin induced lung injury. Loss of mesenchymal CBX5 attenuated fibrosis development, and this effect was accompanied by the downregulation of pathogenic fibroblast genes, including Cthrc1, Col1a1, and Spp1, and by the upregulation of metabolic genes with anti-fibrotic activity such as Ppara and Pparg. scRNA-seq and immunohistochemistry analyses revealed that CBX5 expression was enriched in pathogenic fibroblasts and fibroblastic foci of IPF lungs. Bulk RNA-seq analysis combined with metabolic assessments demonstrated that CBX5 silencing in IPF fibroblasts potently inhibited TGFβ-stimulated glycolysis while enhancing AMPK signaling and mitochondrial metabolism. Finally, interruption of the CBX5 pathway in IPF fibroblasts in vitro and in IPF lung explants ex vivo synergistically potentiated metformin-induced AMPK activation and inhibited collagen secretion. Collectively, our findings identify CBX5 as an epigenetic regulator linking metabolic maladaptation to the persistent activated state of lung fibroblasts during IPF progression.

PMID:39642371 | DOI:10.1165/rcmb.2024-0255OC

Am J Respir Crit Care Med. 2024 Dec 6. doi: 10.1164/rccm.202410-1975ED. Online ahead of print.

NO ABSTRACT

PMID:39642358 | DOI:10.1164/rccm.202410-1975ED

Biomark Insights. 2024 Dec 4;19:11772719241297171. doi: 10.1177/11772719241297171. eCollection 2024.

ABSTRACT

BACKGROUND: Rheumatoid arthritis (RA) is complicated with interstitial lung disease (ILD). Gastroesophageal reflux disease is prevented by Helicobacter pylori infection and is a predisposing factor for idiopathic pulmonary fibrosis. However, the prevalence of H. pylori infection in RA patients with ILD has not been sufficiently investigated.

OBJECTIVE: In this study, we analyzed anti-H. pylori antibodies in RA patients with ILD.

DESIGN: Case-control observational study.

METHODS: Anti-H. pylori antibodies were analyzed in the sera of RA patients using a commercially available enzyme-linked immunosorbent assay kit.

RESULTS: The positivity of anti-H. pylori antibodies in RA with ILD (n = 30 [18.0%], P = .0227), usual interstitial pneumonia (n = 10 [14.3%], P = .0212), and airway disease (n = 30 [18.0%], P = .0227) was significantly lower than that of RA without chronic lung disease (n = 78 [27.5%]). The positivity of anti-H. pylori antibodies was also lower in RA with chronic lung disease (n = 68 [18.2%], P = .0059). Multiple logistic regression analyses showed that the presence of anti-H. pylori antibodies was independently and protectively associated with chronic lung disease in RA.

CONCLUSION: The seroprevalence of H. pylori was lower in RA with ILD. H. pylori infection prevented ILD in patients with RA by protecting them from gastroesophageal reflux disease.

PMID:39640205 | PMC:PMC11618895 | DOI:10.1177/11772719241297171

Cell Commun Signal. 2024 Dec 5;22(1):586. doi: 10.1186/s12964-024-01966-3.

ABSTRACT

Pyroptosis, an inflammatory regulated cell death (RCD) mechanism, is characterized by cellular swelling, membrane rupture, and subsequent discharge of cellular contents, exerting robust proinflammatory effects. Recent studies have significantly advanced our understanding of pyroptosis, revealing that it can be triggered through inflammasome- and caspase-independent pathways, and interacts intricately with other RCD pathways (e.g., pyroptosis, necroptosis, ferroptosis, and cuproptosis). The pathogenesis of pulmonary fibrosis (PF), including idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases, involves a multifaceted interplay of factors such as pathogen infections, environmental pollutants, genetic variations, and immune dysfunction. This chronic and progressive interstitial lung disease is characterized by persistent inflammation, extracellular matrix (ECM) accumulation, and fibrotic alveolar wall thickening, which potentially contribute to deteriorated lung function. Despite recent advances in understanding pyroptosis, the mechanisms by which it regulates PF are not entirely elucidated, and effective strategies to improve clinical outcomes remain unclear. This review strives to deliver a comprehensive overview of the biological functions and molecular mechanisms of pyroptosis, exploring its roles in the pathogenesis of PF. Furthermore, it examines potential biomarkers and therapeutic agents for anti-fibrotic treatments.

PMID:39639365 | DOI:10.1186/s12964-024-01966-3

Nat Commun. 2024 Dec 5;15(1):10624. doi: 10.1038/s41467-024-54997-2.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory scarring disease arising from the maladaptive differentiation of lung stem cells into bronchial epithelial cells rather than into alveolar type 1 (AT1) cells, which are responsible for gas exchange. Here, we report that healthy lungs maintain their stem cells through tonic Hippo and β-catenin signaling, which promote Yap/Taz degradation and allow for low-level expression of the Wnt target gene Myc. Inactivation of upstream activators of the Hippo pathway in lung stem cells inhibits this tonic β-catenin signaling and Myc expression and promotes their Taz-mediated differentiation into AT1 cells. Vice versa, increased Myc in collaboration with Yap promotes the differentiation of lung stem cells along the basal and myoepithelial-like lineages allowing them to invade and bronchiolize the lung parenchyma in a process reminiscent of submucosal gland development. Our findings indicate that stem cells exhibiting the highest Myc levels become supercompetitors that drive remodeling, whereas loser cells with lower Myc levels terminally differentiate into AT1 cells.

PMID:39639058 | DOI:10.1038/s41467-024-54997-2

Am J Respir Crit Care Med. 2024 Dec 5. doi: 10.1164/rccm.202311-2021OC. Online ahead of print.

ABSTRACT

RATIONALE: Idiopathic Pulmonary Fibrosis (IPF) is a lethal disease with limited therapeutic options. FGF21, an endocrine fibroblast growth factor that acts through the FGFR1/KLB pathway, mitigates liver fibrosis.

OBJECTIVES: We hypothesized that FGF21 could exert anti-fibrotic properties in the lung.

METHODS: The concentrations of FGF21 and KLB in the plasma of IPF patients and control subjects were assessed. Pulmonary fibrosis development was assessed in Fgf21-deficient mice as compared to Wild Type littermates, at Day 14 after intra-tracheal injection of bleomycin. We determined the effect of repeated subcutaneous injections of a PEGylated FGF21 analog (PEG-FGF21) at D7, 10, 14 and 17 after bleomycin on the development of pulmonary fibrosis. Mice were sacrificed at D21. The effects of FGF21, alone or with KLB, on apoptosis in MLE15 cells and on the phenotype of human lung fibroblasts were assessed in vitro.

RESULTS: In the plasma of IPF patients, FGF21 concentration was increased, while KLB levels were decreased. Fgf21 deficient mice presented an increased sensitivity to bleomycin, in comparison to their Wild Type littermate. Treatment with PEGylated FGF21 mitigated lung fibrogenesis, as evidenced by a lower injury score, decreased fibrosis markers and pro-fibrotic mediators expression as compared to the control group receiving the diluent. In MLE15 cells, stimulation with FGF21 and KLB inhibited apoptosis, through the decrease of BAX and BIM. Fibroblastic phenotype remained unaltered.

CONCLUSION: Our data indicate a possible anti-fibrotic effect of FGF21 in the lung achieved through the inhibition of alveolar type 2 cells apoptosis.

PMID:39637324 | DOI:10.1164/rccm.202311-2021OC

Proc Natl Acad Sci U S A. 2024 Dec 10;121(50):e2401899121. doi: 10.1073/pnas.2401899121. Epub 2024 Dec 5.

ABSTRACT

Fibrosis drives end-organ damage in many diseases. However, clinical trials targeting individual upstream activators of fibroblasts, such as TGFβ, have largely failed. Here, we target the leukemia inhibitory factor receptor (LIFR) as an "autocrine master amplifier" of multiple upstream activators of lung fibroblasts. In idiopathic pulmonary fibrosis (IPF), the most common fibrotic lung disease, we found that lung myofibroblasts had high LIF expression, and the fibroblasts in fibroblastic foci coexpressed LIF and LIFR. In IPF, fibroblastic foci are the "leading edge" of fibrosis and a key site of disease pathogenesis. TGFβ1, one of the principal drivers of fibrosis, up-regulated LIF expression in IPF fibroblasts. We found that TGFβ1, IL-4, and IL-13 stimulations of fibroblasts require the LIF-LIFR axis to evoke a strong fibrogenic effector response in fibroblasts. In vitro antibody blockade of LIFR on IPF lung fibroblasts reduced the induction of profibrotic genes after TGFβ1 stimulation. Silencing LIF and LIFR reduced profibrotic fibroblast activation following TGFβ1, IL-4, and IL-13 stimulations. We also demonstrated that LIFR amplified profibrotic stimuli in precision-cut lung slices from IPF patients. These LIFR signals were transduced via JAK2, and STAT1 in IPF lung fibroblasts. Together, we find that LIFR drives an autocrine circuit that amplifies and sustains pathogenic activation of IPF fibroblasts. Targeting a single, downstream master amplifier on fibroblasts, like LIFR, is an alternative therapeutic strategy that simultaneously attenuates the profibrotic effects of multiple upstream stimuli.

PMID:39636853 | DOI:10.1073/pnas.2401899121